WO2012044090A2 - Novel aminoquinazoline compound having a protein-kinase inhibiting action - Google Patents

Novel aminoquinazoline compound having a protein-kinase inhibiting action Download PDF

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WO2012044090A2
WO2012044090A2 PCT/KR2011/007194 KR2011007194W WO2012044090A2 WO 2012044090 A2 WO2012044090 A2 WO 2012044090A2 KR 2011007194 W KR2011007194 W KR 2011007194W WO 2012044090 A2 WO2012044090 A2 WO 2012044090A2
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methyl
quinazolin
ylamino
benzimidazol
carboxylic acid
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PCT/KR2011/007194
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French (fr)
Korean (ko)
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WO2012044090A3 (en
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정원근
나정은
임춘영
박철홍
조중명
노성구
이휘성
최종류
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크리스탈지노믹스(주)
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Priority to KR1020137010975A priority Critical patent/KR20130141500A/en
Publication of WO2012044090A2 publication Critical patent/WO2012044090A2/en
Publication of WO2012044090A3 publication Critical patent/WO2012044090A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • New aminoquinazoline compounds with protein kinase inhibitory activity are described in detail below.
  • the present invention relates to novel aminoquinazoline compounds; Pharmaceutical compositions comprising said compounds; And use for the prevention or treatment of diseases associated with abnormal cell reactions induced by protein kinases of the compounds.
  • BACKGROUND Protein kinases are enzymes involved in controlling signal transduction processes that regulate cellular activity through phosphorylation in cells (Hardie and Hanks, The Protein Kinase Facts Book, I and II, Academic Press, San Diego, Calif. , 1995).
  • kinases contain catalytic domains consisting of 250 300 amino acids that are very similar in structure, and are categorized into families such as tyrosine kinases, serine kinases or threonine kinases, depending on the substrates they phosphorylate, and amino acids interact with each of these families.
  • Spleen Tyrosine Kinase plays an important role in the transmission of information at T cell receptors and is a key mediator of immunoreceptor signaling in many inflammatory cells, including mast cells, ⁇ -cells, macrophages and neutrophils. It is known as protein tyrosine kinase (PTK).
  • Immunoreceptors comprising Fc receptors and B-cell receptors are deeply associated with allergic diseases and antibody mediated autoimmune diseases. Thus, pharmacological interference with Syk will be able to treat these allergic and antibody mediated autoimmune diseases.
  • FcsRI has a basic structural commonality with immunoglobulin receptors (T cell receptor and B cell IgM receptor), multichain immune recognition receptor (multichain immune recognition receptor) It belongs to a super family called. Structurally, FcsRI consists of one ⁇ and ⁇ chains and two ⁇ chains, respectively, which covalently bind at sites passing through the cell membrane phospholipid layer. The ⁇ augmentation of FcsRI has a homology domain with two immunoglobulins (Ig) in the extracellular domain and binds with high affinity to the homologous domain IgE on the C-terminal side of the immunoglobulin (Ig) Cfi " J. Biol.
  • the ⁇ chain has a short extracellular domain, most of which is present in the cell, and forms a homodimer by disulfide bonds (S—S bonds). Since ⁇ chains play an important role in intracellular signal transduction, cleavage of intracellular domains can lead to disruption of signal transduction, and ⁇ chains amplify signal transduction, while the ⁇ chain deficiency causes intracellular signal transduction.
  • immunoreceptor tyros ine-based activation mo based on two tyrosine groups in the intracellular domain, respectively tif (ITAM) or antigen receptor activation motif (ARAM)
  • ITAM immunoreceptor tyrosine activation motif
  • the signal generated by the binding of the ligand to the ITAM-containing receptor carries a signal that allows the protein to be replenished from the Src family of non-receptor tyrosine kinases.
  • These kinases phosphorylate tyrosine groups in portions that interact with the SH2 domain on Syk or ZAP-70 in the ITAM sequence.
  • Syk is firmly bound to Lyn's ITAM in tyrosine phosphorylated ⁇ surgery via the SH2 domain. Self-phosphorylation and phosphorylation by Lyn proceed by this binding, and it is known to enhance activity by causing structural change of Syk (J. Biol. Chan., Vol. 270. P. 10498-10502, 1995).
  • Activated Syk induces the formation of adapter molecule complexes or activation of enzymes and transmits signals to common pathways used by many receptors, such as phospholipase CY (PLCY) and MAP kinase (MAPK).
  • PLCY phospholipase CY
  • MAPK MAP kinase
  • PLCy is tyrosine phosphorylated by Syk, phosphatidylinosyl -4,5-diphosphate (PI-4,5-P2), diacylglycerol (DAG) and inosyl 1,4,5-triphosphate (IP3) Hydrolyze with DAG induces activation of protein kinase C (PKC), which induces de-granulation in combination with elevated intracellular calcium concentrations.
  • Syk associates with many adapter molecules that do not have kinase activity and only have an SH2 domain to activate the MAPK superfamily, resulting in arachidonic acid bands via phosphorylation of PLA2.
  • Activation of ERK, p38, JNK, etc. is involved in cytokine production of mast cells through transcription factors such as API (J. Biol. Chew., Vol. 270, p. 16333-16338, 1995).
  • autoimmune diseases such as rheumatoid arthritis, lupus, multiple sclerosis, hemolytic anemia, immune-thrombocytopenic purpura and heparin-induced thrombocytopenia and arteriosclerosis.
  • Many of these diseases cause Fc receptors by antibodies that activate through syk a series of signaling of mast cells, basophils and other immune cells that play a role in the inflammatory response. It is thought to occur through.
  • Rheumatoid arthritis one of the autoimmune diseases, is known to affect about 1% of the total population and is characterized by inflammation of the joints causing the destruction of bone and cartilage.
  • Syk kinase activity has potential therapeutic benefits in the treatment of disorders associated with inappropriate Syk activity, in particular in the treatment and prevention of diseases mediated by Syk.
  • diseases include inflammatory allergies and autoimmune diseases such as asthma, chronic obstructive pulmonary disease (C0PD), adult respiratory distress syndrome (ARDS), ulcerative colitis, Crohn's disease, bronchitis, dermatitis, allergic rhinitis, psoriasis, skin Sclerosis, urticaria, rheumatoid arthritis, multiple sclerosis, cancer, HIV and lupus.
  • the present inventors completed the present invention by discovering a novel aminoquinazoline compound having an excellent inhibitory effect on Syk kinase.
  • An object of the present invention is to provide novel aminoquinazoline derivatives having excellent inhibitory effects on protein kinases.
  • Another object of the present invention is to provide a pharmaceutical composition comprising the aminoquinazoline derivative as an active ingredient.
  • Another object of the present invention is to provide a use for the prevention or treatment of a disease associated with abnormal cell reaction induced by the protein kinase of the aminoquinazoline derivative.
  • Still another object of the present invention is to provide a method for preventing or treating a disease associated with abnormal cell reaction induced by protein kinase, comprising administering an effective amount of the aminozunazoline derivative to a mammal in need thereof.
  • the present invention provides a compound selected from the group consisting of a compound of formula (I) and a pharmaceutically acceptable salt, isomer, hydrate and solvate thereof:
  • W, X and Y are each independently C, N, 0 or S, wherein at least one of W, X and Y is N, and may constitute an aromatic compound, and W, X and Y are each C or N sign In the case, may have a substituent R 3; oo
  • A is selected from the group consisting of hydrogen, halogen, aminocarbonyl, carbonylamino, _C ⁇ , -0-C-, -0-, amino, urea, sulfonyl, sulfoxy, aminosulfonyl and sulfonylamino ;
  • B is hydrogen, d- 5 alkyl, C 2-6 alkenyl, C 5 - 12 aryl, C 5 - 13 heteroaryl, C 3 - 13 cycloalkyl or C 3 - 13, and heterocycloalkyl, where the alkyl, alkenyl , Aryl, heteroaryl, cycloalkyl and heterocycloalkyl are halogen, d- 5 alkyl, halo d- 5 alkyl, c 3-8 cycloalkyl, hydroxy, c s — 12 aryl, c: -5 alkoxy, ⁇ 5 Alkoxy) carbonyl, carboxyl, amino, 5 alkyl) amino, piperidinyl, (d- 5 alkoxy) d- 5 alkyl, morpholinyl, aminocarbonyl, morpholinyl (d- 5 alkyl), (C !
  • Rl, R2 and R3 are each independently hydrogen, halogen, hydroxy, amino, d- 5 alkyl, (: 2 - 6 alkenyl, alkoxyalkyl, C 1-5 amino, aminocarbonyl, carbonyl, amino, sulfonyl, C 5 - 12 aryl, 5-12 c by interrogating aryl, C 5 - 12 bicyclo aryl, C 5 -] 2 bicyclo heteroaryl, C 3 - 12 cycloalkyl or 3-12 membered heterocycloalkyl c, where , Alkyl, alkenyl, alkoxy, amino, aminocarbonyl, carbonylamino, sulfonyl, aryl, heteroaryl, bicycloaryl, bicycloheteroaryl, cycloalkyl and heterocycloalkyl are halogen, hydroxy, amino, d- 5 alkyl, alkoxy, d-5 amine, sulfonyl,
  • the compound of formula (I) Provided as an active ingredient, pharmaceutical composition.
  • the present invention provides a use for the prevention or treatment of a disease associated with abnormal cell reaction induced by the protein kinase of the compound of formula (I).
  • the present invention provides a method for preventing or treating a disease associated with abnormal cell response induced by protein kinase, comprising administering to a mammal in need thereof an effective amount of the compound of formula (I).
  • a disease associated with abnormal cell response induced by protein kinase comprising administering to a mammal in need thereof an effective amount of the compound of formula (I).
  • the compound of formula (I) of the present invention may be represented by a compound of formula (i- a ):
  • D is C or N
  • R 1, R 2 and R 3 are each independently hydrogen, halogen, hydroxy, amino, C 1-5 alkyl, C 2 -S alkenyl, CHSalkoxy, d- 5 amino, aminocarbonyl, carbonylamino, sulfonyl,
  • R4 and R5 are each independently hydrogen, d- 5 alkyl, d- 5 alkylamino, C 2 - 6 alkenyl, C 5 - 12 aryl, C 5 - 12 bicyclo aryl, C 5 - 12 bicyclo heteroaryl, C 3 - 12 cycloalkyl or C 3 - and 12 heterocycloalkyl, where the alkyl, amino, alkenyl, aryl, bicyclo aryl, bicyclo heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with hydroxy, amino, alkyl amines, alkyl, C 2 - 6 alkenyl, C 5 -
  • aryl, C 5 - 12 bicyclo aryl, C 5 - 12 bicyclo heteroaryl, C 3 - 12 cycloalkyl, and c 3 - i2 heterocycloalkyl may be substituted with one or more substituents selected from the group consisting of alkyl and;
  • R4 and R5 are connected to each other HJ carbocycle, C 2 - 6 heterocyclyl, C 5 - 12 by-cycle or a C 5 - 12 may form a hetero-by-cycle, carbocycle
  • heterocycle, by-cycle and heteroaryl-by-cycle is halogen, hydroxy ethoxy, amino, alkylamine, d- 5 alkyl, C 2 - 6 alkenyl, C 5 - 12 aryl, C 5 - 12 bicyclo aryl, C 5 - 12 aryl bicyclo by Tero , C 3-12 cycloalkyl, and C 3 - and may be substituted with one or more substituents selected from the group consisting of 12-heterocycloalkyl;
  • R4 and R5 are C 2 - 6 by interrogating cycle or C 5 -
  • the hetero element is N case can be optionally substituted with substituents R6, wherein, R6 is hydrogen, d- 3 lower alkyl or C 3 - 6 may be substituted with cycloalkyl, lower alkyl or cycloalkyl substituted by one or more halogens here.
  • Preferred compounds in the compounds of formula (Ia) may be represented by compounds of formula ( ⁇ -a ') wherein D is nitrogen: R2011 / 007194
  • R 1 is hydrogen; Halogen, for example chloro or fluoro; And d- 5 alkyl and alkoxy optionally substituted with one or more halogens.
  • C ! 5 alkyl is methyl, ethyl or isopropyl
  • the d- 5 alkoxy is methoxy, epoxy or isopropoxy
  • halogen substituted C 1-5 alkyl is CF 3
  • halogen substituted alkoxy is 0CF 3 .
  • R2 is hydrogen; halogen; And optionally substituted by one or more halogen, d- 5 alkyl, C 1-5 alkoxy, (5-amino and C 3 - 6 are each individually selected from the group consisting of cycloalkoxy;
  • R3 is hydrogen; And optionally substituted by one or more halogen, d-5 alkyl and C 3 - 12 are each individually selected from the group consisting of cycloalkyl, e.g., (5-alkyl is methyl, ethyl or isopropyl, the 3 ⁇ 4- 12 cycloalkyl Cyclopropyl or cyclobutyl.
  • cycloalkyl e.g., (5-alkyl is methyl, ethyl or isopropyl, the 3 ⁇ 4- 12 cycloalkyl Cyclopropyl or cyclobutyl.
  • R4 and R5 are each independently hydrogen; And optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, morpholine, piperidine, piperazine, alkylpiperazine and C 3 H 5 cycloalkylpiperazine ( 5 alkyl, d- 5 alkyl amino, C 2 - 6 alkenyl, C 5 - 12 aryl, C 5 - 12 bicyclo aryl, C 5 - 12 bicyclo by interrogating aryl, C 3 _ 12 cycloalkyl, and 12 selected from the group consisting of heterocycloalkyl Become;
  • R4 and R5 may be connected to each other to form a cycle, the cycle may include one or more heteroatoms selected from the group consisting of N, 0 and S, when the hetero element is N substituent R6 It may be substituted with, wherein R6 is hydrogen; And in with one or more halogen, preferably chloro or fluoro, optionally substituted, (5 alkyl, C 3 - 12 cycloalkyl, and C 3 - 12 cycloalkyl, and it may be selected from the group consisting of -C 1-5 alkyl, such as For example, the alkyl may be methyl, ethyl or And isopropyl, wherein c 3-12 cycloalkyl is cyclopropyl, the C 3 - 12 cycloalkyl, -C- 5 alkyl is cyclopropylmethyl.
  • the compound of formula (I) of the present invention may be represented by a compound of formula (Ib):
  • X is C or N
  • R 1 is hydrogen; Halogen, for example chloro or fluoro; And d- 5 alkyl and d- 5 alkoxy, optionally substituted with one or more halogens, for example, wherein ( 5 alkyl is methyl, ethyl or isopropyl, and d- 5 alkoxy is methoxy , Ethoxy or isopropoxy, halogen substituted C 1-5 alkyl is CF 3 and halogen substituted d- 5 alkoxy is —0CF 3 .
  • R2 is hydrogen; halogen; And C- 5 alkyl optionally substituted with one or more halogens.
  • alkoxy, (5-amino and C 3 - 6 are each individually selected from the group consisting of cycloalkoxy;
  • R3 is hydrogen; And optionally substituted by one or more halogen, d- 5 alkyl, C 3 - is selected from the group consisting of 12-cycloalkyl, for example, the C 5 alkyl is methyl, ethyl or isopropyl, the C 3 - 12 cycloalkyl Alkyl is cyclopropyl or cyclobutyl.
  • R4 and R5 are each independently hydrogen; And halogen, hydroxy, amino, morpholine, piperidine, piperazine, d- 6 alkyl piperazine and C 3 - 6 cycloalkyl piperazine optionally with one or more substituents selected from the group consisting of a substituted, 5 d- Alkyl , d- 5 alkylamino, C 2 - 6 alkenyl, C 5 - 12 aryl, C 5-12 bicyclo aryl, C 5 - 12 bicyclo by interrogating aryl, C 3 - 12 cycloalkyl, and c 3 to 12 eu from the group consisting of cycloalkyl, Tero Selected;
  • R4 and R5 may be connected to each other to form a cycle, the cycle may include one or more hetero elements selected from the group consisting of N, 0 and S, when the hetero element is N to substituent R6 Which may be substituted, wherein R6 is hydrogen; And at least one halogen, preferably optionally substituted with chloro or fluoro, d- 5 alkyl, C 3 - 12 cycloalkyl, and C 3 - 12 may be selected from the group consisting of cycloalkyl, -d- 5 alkyl, such as for example, the d- 5 alkyl is methyl ethyl or isopropyl, the C 3 - I2 cycloalkyl is cyclopropyl, the C 3 - 12 cycloalkyl, -d- 5 alkyl is cyclopropylmethyl.
  • the compound of formula (I) of the present invention may be represented by a compound of formula (Ic):
  • R 1 is hydrogen; Halogen, for example chloro or fluoro; And d- 5 alkyl and d- 5 alkoxy, optionally substituted with one or more halogens, for example, wherein ( 5 alkyl is methyl, ethyl or isopropyl, and d- 5 alkoxy is methoxy , Ethoxy or isopropoxy, halogen substituted d- 5 alkyl is CF 3 and halogen substituted C 1-5 alkoxy is -0CF 3 .
  • R2 is hydrogen; Halogen, for example chloro or fluoro; And optionally substituted by one or more halogen, alkoxy and C 3 - 6 from a group consisting of cycloalkoxy Selected;
  • R3 is hydrogen; And d- 5 alkyl and C 3-12 cycloalkyl, optionally substituted with one or more halogens, for example, the d- 5 alkyl is methyl, ethyl or isopropyl, and C 3 _ 12 Cycloalkyl is cyclopropyl or cyclobutyl.
  • R7 and R8 are each independently hydrogen; And alkyl and -12 cycloalkyl, optionally substituted with one or more halogens, for example, the d- 5 alkyl is methyl, ethyl or isopropyl, and the C 3-12 cycloalkyl is cyclopropyl Or cyclobutyl.
  • Z is selected from the group consisting of a covalent bond, -CHR6, -0-, -NR6- and -S0 2- ;
  • the R6 is an optionally as chloro or fluoro in the at least one halogen, for example, substitution, C- 5 alkyl, C 3 - 12 cycloalkyl, and C 3 - 12 cycloalkyl, -d- selected from the group consisting of alkyl 5
  • the d- 5 alkyl is methyl, ethyl or isopropyl, C 3 ⁇
  • Cycloalkyl is cyclopropyl, a C 3 - 12 cycloalkyl, -d- 5 alkyl is cyclopropylmethyl.
  • the compound of formula (I) of the present invention may be represented by a compound of formula (Id):
  • R 1 is hydrogen; Halogen, for example chloro or fluoro; And d- 5 alkyl and d- 5 alkoxy, optionally substituted with one or more halogens, for example the C 1-5 alkyl is methyl, ethyl or isopropyl, the d- 5 alkoxy Is methoxy, ethoxy or isopropoxy, the d- 5 alkyl substituted with halogen is CF 3 and the -5 alkoxy substituted with halogen is -0CF 3 .
  • R2 is hydrogen; Halogen, for example chloro or fluoro; And optionally substituted by one or more halogen, d- 5 alkoxy and C 3 - 6 is selected from the group consisting of cycloalkoxy;
  • R3 is hydrogen; And halogen, d- 5 alkyl, d- 5 alkoxy, C 3 - 6 cycloalkoxy, d- 6 alkylamino, - 12 cycloalkyl, C 3 - 12 heterocycloalkyl, C 5 - 12 aryl and C 5 - 12 hetero optionally substituted with one or more substituents selected from the group consisting of aryl, 5-d- alkyl, - 5 alkoxy, C 3 - 6 cycloalkoxy, amino, d- 6 alkylamino, - 12 cycloalkyl, C 3 - 12 heterocycloalkyl It is selected from - the group consisting of 2-heteroaryl -, C 5 - 12 aryl and C 5.
  • the term "halo" or "halogen” means fluoro, bromo, chloro or iodo.
  • alkyl refers to a linear or branched saturated C to 3 ⁇ 4 hydrocarbon radical chain. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl or isopentyl.
  • alkynyl refers to a divalent hydrocarbon group having two hydrogens removed from an alkyne having a triple bond, and specific examples include, but are not limited to, ethynyl, propynyl, and the like.
  • aryl as used herein includes fused groups such as naphthyl, phenanthrenyl and the like as well as monocyclic or bicyclic aromatic rings such as phenyl, substituted phenyl and the like. Specific examples include, but are not limited to, phenyl, toluyl, xylyl, biphenyl and naphthyl.
  • heteroaryl means a monocyclic or bicyclic or higher aromatic group containing a heteroatom selected from oxygen, nitrogen and sulfur.
  • monocyclic heteroaryls include furyl, thienyl, thiazolyl, pyrazolyl, isoazolyl, oxazolyl, isoxazolyl, pyryl, triazolyl, tetrazolyl, imidazolyl, nooxadia Jolyl, 1 2 4 _oxadiazolyl, 1 2 3 _oxadiazolyl, 1, 3, 5-thiadiazolyl, 1,2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2, 4-triazineyl, 1,2,3 ⁇ triazineyl, 1,3, 5-triazineyl, cinnaline, putridinyl, purinyl, 6,7
  • cycloalkyl as used herein, means cyclic alkyl. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, and cyclonuclear cylinders.
  • heterocycloalkyl refers to monocyclic or bicyclic or higher cyclic alkyl containing heteroatoms selected from oxygen, nitrogen and sulfur.
  • mono heterocycloalkyl include, but are not limited to, piperidine, morpholine, thiamorpholine, pyrrolidine, imidazolidine, tetrahydrofuran, piperazine, and the like.
  • alkoxy refers to the group -0R a , where 1 ⁇ is alkyl as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, and the like. Specific examples of the preferred compounds according to the invention are the same as those listed in Table 1 below. TABLE 1
  • Morpholine-4 carboxylic acid [1-ethyl-2-methyl-
  • the compounds of formula (I) according to the invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids, which include non-toxic acid addition salts containing pharmaceutically acceptable anions.
  • acid for example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, inorganic acids, such as hydroiodic acid, tartaric acid, formic acid, citric acid, acetic acid, tri, chloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, Acid addition salts formed by organic carbon acids such as fumaric acid and maleic acid, methanesulfonic acid, benzenesulfonic acid, sulfonic acids such as P-toluenesulfonic acid or naphthalenesulfonic acid, and the like, particularly preferably sulfuric acid, methanesulfonic acid or hydrofluoric acid
  • the acid addition salt formed by this is mentioned.
  • Pharmaceutically acceptable salts of the compounds of formula (I) are conventional Methods can be prepared and used from compounds of formula (I). Specifically, pharmaceutically acceptable salts according to the present invention may be prepared by dissolving a compound of formula (I) in a water-miscible organic solvent such as acetone, methanol, ethane, or acetonitrile and adding an excess of an organic acid or an inorganic acid. It can be prepared by adding an aqueous acid solution followed by precipitation or crystallization. This mixture can then be evaporated and dried to evaporate the solvent or excess acid to obtain additional salts or to precipitate prepared salts by suction filtration.
  • a water-miscible organic solvent such as acetone, methanol, ethane, or acetonitrile
  • the compounds of formula (I) according to the invention can be used as hydrates and solvates which can be prepared therefrom.
  • the compound of formula (I) according to the present invention may have an asymmetric carbon center, so that not only pharmaceutically acceptable salts thereof, but also can be prepared therefrom
  • R or S isomers, racemic compounds, diastereomers, isomeric mixtures, and individual diastereomers, and these solvates, hydrates, isomers and mixtures thereof are also included in the scope of the present invention.
  • the compound of formula (I), or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof may be SYK, JA 3, FLT3, FLT2, PDGFR (PDGFRA), TRKA (NTRKl), KDR, CD 2 / cycA, AurA (AURKA) can inhibit the activity of protein kinases such as ERK, PI3K, Raf, PYK2 and RET, and thus can be used for the treatment of diseases associated with abnormal cell reactions induced by said protein kinases.
  • protein kinases such as ERK, PI3K, Raf, PYK2 and RET
  • the present invention provides a method for the prevention of diseases associated with abnormal cellular responses induced by protein kinases of a compound of formula (I), and a compound selected from the group consisting of pharmaceutically acceptable salts, isomers, hydrates and solvates thereof. Or for therapeutic use.
  • the present invention is selected from the group consisting of the compound of formula (I), and pharmaceutically acceptable salt isomers, hydrates and solvates thereof.
  • Provided are methods for the prevention or treatment of diseases associated with abnormal cell reactions induced by protein kinases, comprising administering an effective amount of a compound to a mammal in need thereof.
  • the present invention also provides an activity inhibitor of protein kinase comprising the compound of formula (I), and a compound selected from the group consisting of pharmaceutically acceptable salts, isomers, hydrates and solvates as an active ingredient. .
  • the present invention is a protein kinase comprising a compound selected from the group consisting of the compound of formula (I), pharmaceutically acceptable salts, isomers, hydrates and solvates and a pharmaceutically acceptable carrier as an active ingredient It provides a pharmaceutical composition for the prevention or treatment of diseases associated with abnormal cell reaction induced by.
  • the disease includes all diseases that can be caused by overexpression of protein kinases and thus abnormal cell responses, and specifically, immune diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, neuropsychiatric disorders, and degenerative brain. Diseases, cancer, heart disease, allergic diseases, asthma, Alzheimer's and hormone-related diseases. However, it is not limited thereto.
  • the pharmaceutical composition may comprise a pharmaceutically acceptable carrier or vehicle together.
  • compositions of the present invention may be formulated according to conventional methods and may be used in various oral dosage forms, such as tablets, pills, powders, tablets, syrups, emulsions, microemulsions, or intramuscular, intravenous or subcutaneous administration. It may be prepared in a parenteral dosage form.
  • examples of the carrier usable include starch, calcium carbonate, sucrose, lactose, gelatin, magnesium stearate, talc and the like.
  • liquids for oral administration such as suspensions, liquid solutions, emulsions or syrups
  • the carrier usable in the preparation of the preparation include water which is a simple diluent, diluents such as liquid paraffin and wetting agents, sweeteners, fragrances or preservatives.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations or suppositories.
  • the carrier usable when prepared with the non-aqueous solvent or the suspension solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like.
  • Carriers usable in this case include witepsol, macrogol, twenty-one, cacao butter, laurin butter, glycerol or gelatin.
  • the human dose of the active ingredient such as the compound according to the present invention may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, when the weight is 70 kg based on an adult patient It is generally 1.0 mg to 10,000 mg / day, preferably 10 mg to 3,000 nig / day, and may be dividedly administered once to several times a day at regular intervals.
  • the compound of formula (I) may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, when the weight is 70 kg based on an adult patient It is generally 1.0 mg to 10,000 mg / day, preferably 10 mg to 3,000 nig / day, and may be dividedly administered once to several times a day at regular intervals.
  • the compound of formula (I) may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, when the weight is 70 kg based on an adult patient It is generally 1.0 mg to 10,000 mg / day, preferably 10 mg to
  • W is —C—R 3
  • X is N
  • Y is NH
  • A is —NH—C 0—, which may be prepared by a manufacturing process as shown in Scheme 1 below:
  • R1, R2, R3 and B are as defined in formula (I) above.
  • reaction formula 1 through the nitration reaction of 2-fluoro benzoic acid (1) with a nitric acid and sulfuric acid mixture as a solvent, 3,5-dinitrol 2 one fluorobenzoic acid (2 ), And then treated with ammonia water to obtain 3,5'dinitrotropy 2-aminobenzoic acid (3). It is heated in an aqueous solution of ammonium sulfide to selectively substitute only the 3-nitro group with an amino group. Diamino # 5 one nitrobenzoic acid (4) can be manufactured. 2,3—diamino ⁇ 5 ⁇ prepared above 0
  • the benzoimidazole derivatives (6) can be obtained by reacting nitrobenzoic acid with H R3 (5) (for example, aldehyde, carboxylic acid or carboxylic anhydride) using ethanol as a solvent and reflux stirring.
  • H R3 (5) for example, aldehyde, carboxylic acid or carboxylic anhydride
  • the benzimidazole derivative prepared above was reacted in the presence of dimethylsulfoxide (DMF), and dichloromethane (DMC) and tetrahydrofuran (THF) under oxalyl chloride conditions to obtain an acid chloride, Treatment of the id can yield azide derivatives (7) of benzimidazole.
  • DMF dimethylsulfoxide
  • DMC dichloromethane
  • THF tetrahydrofuran
  • the compound (9) obtained above is subjected to polymerization reaction with a quinazoline derivative (for example, 2-chloro quinazoline compound (10)) to produce an amino quinazoline compound (11).
  • a quinazoline derivative for example, 2-chloro quinazoline compound (10)
  • the prepared amino quinazoline compound (11) decomposes the carbamate using an aqueous sodium hydroxide solution to prepare a compound (12) in which an amino group is introduced at the 4-position of benzimidazole.
  • the compound of formula (I) of the present invention can be prepared by reacting the compound of the prepared compound (12) in a halocarbonyl compound (13) and a solvent.
  • the compound of formula (I) (in formula (I), W is -C-R3, X is N, Y is NH, and A is -NH-C0-) It can be prepared by the manufacturing process as shown in Banung Formula 2:
  • R1, R2, R3 and B are as defined in formula (I).
  • the carbamate intermediate of nitro benzimidazole (ie compound (9)) prepared in the manner described in the reaction formula 1 was treated with an aqueous sodium hydroxide solution to prepare a compound (14). do.
  • the compound (15) was prepared by introducing a halocarbonyl group into the 4-position amino group of the compound (14), and then the nitro group of the compound was subjected to hydrogenation reaction using a palladium catalyst or reduction reaction using iron / ammonium chloride.
  • Compound (16) can be prepared by reduction with an amino group.
  • the compound of formula (I) of the present invention can be prepared by polymerizing the compound (16) with a quinazoline derivative (for example, 2-chloro quinazoline compound (10)).
  • a quinazoline derivative for example, 2-chloro quinazoline compound (10).
  • R3 and B are as defined in formula (I).
  • the 1-alkyl benzimidazole derivative can be prepared according to the preparation method as shown in Scheme 4 below.
  • A, B and R3 are as defined in formula (I). Specifically, after dissolving 1H benzimidazole in acetone, the compound (8) or the final compound (I) prepared in Scheme 1 was added with K0H 2 equivalents prepared in a mortar and stirred for 30 minutes at phase silver. Subsequently, 1 equivalent of haloalkanes (for example, methane iodide, chloromethane, ethane iodide, chloroethane or bromoethane) is added to the reaction mixture. After dropwise addition, the mixture was stirred under reflux for 3 hours.
  • haloalkanes for example, methane iodide, chloromethane, ethane iodide, chloroethane or bromoethane
  • the reaction mixture was concentrated, distilled with water, extracted with ethyl acetate (EA), dried over anhydrous Na 2 S3 ⁇ 4 and concentrated under reduced pressure.
  • the product was obtained by chromatography using silica and ethyl acetate / nucleic acid or methanol / dichloromethane.
  • the quinazoline derivative may be prepared according to the following preparation method. Specifically, in Scheme 1 or 2, the quinazoline derivative (eg, 3-chloro quinazoline) that can be used in the polymerization reaction with the benzimidazole compound can be prepared according to the method described in the following reaction formula 5 or 6 have:
  • R1 and R2 are as defined in formula (I) above.
  • 2-aminobenzoic acid is heated with urea using N-methylpyrrolidone (NMP) or phenol as a solvent to synthesize 1,3-dihydroxy quinazoline, and then P0C1 3 1,3-dichloro quinazoline can be synthesized by refluxing and stirring using as a solvent.
  • NMP N-methylpyrrolidone
  • P0C1 3 1,3-dichloro quinazoline can be synthesized by refluxing and stirring using as a solvent.
  • the prepared 1,3-dichloro quinazoline can be synthesized by hydrogenation in the presence of a palladium catalyst or by selectively removing chlorine groups under Zn and N3 ⁇ 4 conditions.
  • R1 and R2 are as defined in formula (I) above.
  • 2-aminobenzaldehyde is heated together with urea using NMP as a solvent to synthesize 3-hydroxy musazolin.
  • 3 -chloro quinazoline can be synthesized by refluxing and stirring using P0C1 3 as a solvent.
  • 2 ⁇ chloroquinazoline derivatives can be prepared according to the scheme described in the following formula:
  • the 2-aminobenzoic acid (1) was reacted in the presence of urea and phenol to prepare diquinazolone (2), which was obtained from P0C! 2,4-dichloro quinazoline (3) can be manufactured by refluxing and stirring 3 as a solvent.
  • the prepared 2,4-dichloro quinazoline (3) can selectively remove chlorine groups under Zn and NH 3 conditions to synthesize 2-chloro quinazoline.
  • Example I Preparation of 2-dimethylamino-N- [2-methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -acetamide 1-1: 2-chloroquinazoline derivative
  • Diquinazolone (2) (114 g, 0.647 ⁇ ol) prepared in step 1 was mixed evenly in a mixture of P0C1 3 (300 mL) and ⁇ , ⁇ -dimethylaniline (45.6 mL, 0.356 mol) for 5 hours. Stirred at reflux. The reaction mixture was poured into ice, and the resulting solid product was obtained by filtration, washed with water and dried under vacuum to give 2,4-dichloroquinazolin (3) (124 g) in 90% yield.
  • Fuming nitric acid (4.25 L) was slowly added dropwise to fuming sulfuric acid (20% SO 3 , 9.0 L) in which the reaction vessel was cooled with ice. At this time, the internal temperature was not allowed to exceed 40 ° C. After adding nitric acid dropwise, the cooling vessel was removed and 2—fluoro benzoic acid (1.77 kg, 12.6 mol) was added. The reaction mixture prepared above was heated to 12 CTC for 2 hours, and then cooled to room temperature, and the reacted reaction mixture was poured into an amount of ice. The solid product formed at this time was obtained by filtration, washed with water and dried in vacuo to give 3,5'dinitro-2-fluorobenzoic acid (2) as a white solid (1.9 kg) in 65% yield.
  • step 3 5-dinitro-2-fluorobenzoic acid (1.9 kg, 8.26 mol) prepared in step 1 was mixed with ammonium hydroxide solution (25%, 20 L) and then at room temperature for 1 hour. Stirred. The solid product formed was filtered off and mixed with water. The mixture was acidified to pH 4 by addition of 4 normal aqueous hydrochloric acid solution. The solid was filtered off and washed with water to give 2-amino-3, 5-dinitrobenzoic acid (3) (1.8 kg) as a yellow solid in 96% yield.
  • the resulting solid obtained by acidification with acetic acid at 5 ° C. was filtered and washed with water.
  • 2,3-diamino-5-nitrobenzoic acid 600 mg, 3.05 ⁇ l ol prepared in A was prepared After dissolving in acetic anhydride (7.0 mL), 3N hydrochloric acid (20 mL) was slowly added dropwise at 0 0 C, followed by stirring under reflux for 30 minutes. After cooling to room temperature, the solid was filtered off. The filtrate was concentrated under reduced pressure and then dissolved in an aqueous sodium hydroxide solution (0.5 N, 6 mL). The resulting solid was acidified by addition of acetic acid and the resulting solid was dried under reduced pressure to give a black solid 2-methyl-6-nitro-lH-benzimidazole-4-carboxylic acid as 71% aqueous (480 mg). The obtained solid was dried several times after the addition of toluene, followed by drying under reduced pressure.
  • the carboxylic acid was mixed with a 4: 1 (v / v) solution of MC and tetrahydrofuran (THF), followed by the dropwise addition of 1.6 equivalents of oxalyl chloride and the catalytic amount of DMF. After stirring for about 3 hours, the mixture was concentrated under reduced pressure, and the remaining material was mixed with MC and THF 4: 1 (v / v) solution, and then primary or secondary amine was added dropwise. After stirring for 5 hours at room temperature, washed with water, dried over anhydrous MgS and concentrated under reduced pressure. This was separated by chromatography to obtain a carbonyl amide derivative.
  • Example I using the starting material to each of the following table
  • Morpholin-4-yl-methane is 2H), 3.62 (m, 4H), 3.34 (m, 4H),
  • Step 1 (2-Methyl-6-nitro-lH-benzimidazol-4-yl) -carbamic acid ethyl ester 2-methyl-6-nitro-lH-benzimidazole prepared in B of step 1-2 above -4- Carboxylic acid (100 mg, 0.45 ⁇ l ol) was dissolved in THF (4 mL), followed by Et 3 N (0.19 mL, 1.35 ⁇ l ol) and diphenylphosphoryl azide (DPPAX0.194 mL, 0.90 ⁇ l ol). Added dropwise. The reaction mixture was stirred under reflux for 3 hours under nitrogen, followed by dropwise addition of ethanol (0.13 mL, 2.23 mmol), followed by stirring under reflux for 10 hours.
  • ethanol 0.13 mL, 2.23 mmol
  • reaction catalyst was filtered through celite, the filtrate was concentrated under reduced pressure, purified by column chromatography using silica and DCM / MeOH 50-30: 1 developing solution (6-amino-2-methyl-1H-benz). Imidazol-4-yl) -carbamic acid ethyl ester (34 g, 58%) as a white solid.
  • Example II was used to prepare the compounds of the examples set forth in Table 3 below, respectively using the corresponding starting materials.
  • Morpholine-4-carboxylic acid 9.65 (s, IH), 9.19 (s, IH), 8.25 (s,
  • Piperazine-1 carboxylic acid 9.67 (s, IH), 9.19 (s, IH), 8.10-
  • Morpholine—4 carboxylic acid 3 ⁇ 4 NMR (300 MHz, DMS0-d 6 ) 10.02 (s,
  • Morpholine-4-carboxylic acid 9.63 (s, IH), 9.18 (s, IH), 8.14 (s,
  • Morpholine—4-sulfonic acid [2- 12.20 (s, IH), 9.89 (s, IH) '9.22 (s,
  • Methyl-quinazolin-2-12.05 (s, IH), 9.70 (s, IH), 9.30 (s,
  • Methyl-quinazolin-2-IH 8.16 (s, IH), 7.86 (s, IH), 7.75-

Abstract

The present invention relates to: a novel aminoquinazoline compound having an outstanding inhibiting action against protein-kinase; use of the compound in preventing or treating diseases associated with abnormal cell responses induced by protein-kinase; a pharmaceutical composition comprising the compound; and a treatment method in which the compound is used. The compound of the present invention can be used to advantage in preventing or treating diseases associated with abnormal cell responses induced by protein-kinase.

Description

단백질 키나제 억제 활성을갖는신규한아미노퀴나졸린화합물  New aminoquinazoline compounds with protein kinase inhibitory activity
발명의 분야 본 발명은 신규한 아미노퀴나졸린 화합물; 상기 화합물을 포함하는 약학 조성물; 및 상기 화합물의 단백질 키나제에 의해 유도된 비정상적인 세포 반웅과 관련된 질환의 예방 또는 치료용 용도에 관한 것이다. 배경기술 단백질 키나제는 세포내에서 인산화 과정을 통해 세포 활동을 조절하는 신호 전달 과정을 제어하는 데 관련된 효소들이다 (Hardie and Hanks, The Protein Kinase Facts Book, I and II， Academic Press, San Diego, Calif. , 1995) . 거의 모든 키나제는 구조적으로 매우 유사한 250 300개의 아미노산으로 이루어진 촉매 도메인을 포함하고 있으며， 이들이 인산화하는 기질에 따라 타이로신 키나제, 세린 키나제 또는 트레오닌 키나제 등의 패밀리로 분류하며, 이들 각각의 패밀리와 상웅하는 아미노산 서열들이 확인된 바 있다 (Hanks & Hunter, (1995), FASEB J. , 9:576-596; Knighton et al .， (1991), Science, 253:407-414; Hiles et al . , (1992)， Cell, 70:419-429; unz et al . , (1993)ᅳ Cell, 73：585~596； 및 Garcia- Bust os et al . , (1994), EMB0 J. , 13:2352-2361). FIELD OF THE INVENTION The present invention relates to novel aminoquinazoline compounds; Pharmaceutical compositions comprising said compounds; And use for the prevention or treatment of diseases associated with abnormal cell reactions induced by protein kinases of the compounds. BACKGROUND Protein kinases are enzymes involved in controlling signal transduction processes that regulate cellular activity through phosphorylation in cells (Hardie and Hanks, The Protein Kinase Facts Book, I and II, Academic Press, San Diego, Calif. , 1995). Almost all kinases contain catalytic domains consisting of 250 300 amino acids that are very similar in structure, and are categorized into families such as tyrosine kinases, serine kinases or threonine kinases, depending on the substrates they phosphorylate, and amino acids interact with each of these families. Sequences have been identified (Hanks & Hunter, (1995), FASEB J., 9: 576-596; Knighton et al., (1991), Science, 253: 407-414; Hiles et al., (1992) Cell, 70: 419-429; unz et al., (1993) ᅳ Cell, 73: 585-596; and Garcia-Bust os et al., (1994), EMB0 J., 13: 2352-2361).
수많은 질환이 단백질 키나제의 비정상적인 발현， 작용과 관련된 비정상적인 세포 반웅에 관련되어 있다. 이러한 질환의 예로서， 자가면역 질환， 염증 질환, 골 질환， 대사 질환， 신경학적 및 신경퇴행성 질환， 암， 심혈관 질환, 알레르기， 천식, 알츠하이머 및 호르몬관련 질환이 포함된다. 이에 따라, 단백질 키나제의 억제제를 이용하여 비정상적인 세포 반웅을 조을함으로써 상기 질환들의 치료제로 사용하기 위한 노력이 진행되어 왔다. 비장 티로신 키나아제 (Spleen Tyrosine Kinase, Syk)는 T 세포 수용체에서의 정보 전달에 있어서 중요한 역할을 하며， 비만 세포, Β-세포， 대식구 및 호중구를 포함하는 다수의 염증 세포에서 면역수용체 신호전달의 핵심 매개체로서 알려진 단백질 티로신 키나제 (Protein tyrosine kinase; PTK)이다. Numerous diseases are involved in abnormal cellular reactions associated with abnormal expression and action of protein kinases. Examples of such diseases include autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies, asthma, Alzheimer's and hormone-related diseases. Accordingly, efforts have been made to use the inhibitors of protein kinases to treat abnormal cell reactions and to use them as therapeutic agents for these diseases. Spleen Tyrosine Kinase (Syk) plays an important role in the transmission of information at T cell receptors and is a key mediator of immunoreceptor signaling in many inflammatory cells, including mast cells, Β-cells, macrophages and neutrophils. It is known as protein tyrosine kinase (PTK).
Fc 수용체 및 B-세포 수용체를 포함하는 면역수용체는 알레르기 질환 및 항체 매개성 자가면역 질환과 깊게 연관되어 있다. 이에 따라， Syk를 약리학적으로 간섭함으로써 이러한 알레르기 질환 및 항체 매개성 자가면역 질환들을 치료할 수 있을 것이다.  Immunoreceptors comprising Fc receptors and B-cell receptors are deeply associated with allergic diseases and antibody mediated autoimmune diseases. Thus, pharmacological interference with Syk will be able to treat these allergic and antibody mediated autoimmune diseases.
구체적으로， 상기 수용체와 관련된 신호전달과정에 관련된 사항을 살펴보면， FcsRI는 면역글로불린 수용체 (T 세포 수용체 및 B 세포 IgM 수용체)와 기본 구조적 공통성을 지니며， 멀티사술 면역 인지 수용체 (multichain immune recognition receptor)라 불리는 수퍼 패밀리에 속한다. 구조적으로 FcsRI는 세포막 인지질층을 통과하는 부위에서 비공유 결합하는 각각 1개의 α 및 β사슬과， 2개의 γ사슬로 이루어진다. FcsRI의 α사술은 세포 외 도메인에 2개의 면역 글로불린 (Ig)과 상동 도메인을 가지며， 면역 글로불린 (Ig)의 C 말단측의 상동 도메인 IgE와 높은 친화성으로 결합한다 Cfi". J.Biol. Chem. , 266, 1991， p.2639- 2646) . 한편， γ 사슬은 세포외 도메인은 짧고, 그의 대부분이 세포내에 존재하며 , 다이설파이드 결합 (S— S 결합)에 의해 동종 이합체를 형성하고 있는데, γ사슬은 세포내 신호 전달에 중요한 역할을 하므로 세포 내 도메인의 절단은 신호 전달의 중단을 초래할 수 있다. 또한, β 사슬은 신호 전달을 증폭하는 작용을 하며， β사슬의 결손은 세포내 신호 전달을 감소시킨다. β 및 Υ사슬에는 효소 활성은 없고， 각각 세포내 도메인에는 2개의 티로신 기를 기초로 한 특이적인 펩티드 서열 (면역수용체 티로신 활성화 모티프 (immunoreceptor tyros ine-based activation motif; ITAM) 또는 항원수용체 활성화 모티프 (antigen receptor activation motif; ARAM))가 존재한다. 면역수용체 티로신 활성화 모티프 (ITAM)-매개 신호전달은 면역 세포의 면역 수용체 (τ-세포 수용체， Β—세포수용체 및 Fc 수용체) 및 혈소판 내의 GPVI 및 FcyRIIa에서 활성화된 신호를 세포 내의 다음 단계 키나제 (Syk 및 ZAP-70)로 중계하는 역할을 한다 (Underhill, D.M and Goodridge, H. S. , Trends Immunol . , 28：66 73, 2007) . Specifically, looking at the matter related to the signaling process associated with the receptor, FcsRI has a basic structural commonality with immunoglobulin receptors (T cell receptor and B cell IgM receptor), multichain immune recognition receptor (multichain immune recognition receptor) It belongs to a super family called. Structurally, FcsRI consists of one α and β chains and two γ chains, respectively, which covalently bind at sites passing through the cell membrane phospholipid layer. The α augmentation of FcsRI has a homology domain with two immunoglobulins (Ig) in the extracellular domain and binds with high affinity to the homologous domain IgE on the C-terminal side of the immunoglobulin (Ig) Cfi " J. Biol. , 266, 1991, p.2639-2646) On the other hand, the γ chain has a short extracellular domain, most of which is present in the cell, and forms a homodimer by disulfide bonds (S—S bonds). Since γ chains play an important role in intracellular signal transduction, cleavage of intracellular domains can lead to disruption of signal transduction, and β chains amplify signal transduction, while the β chain deficiency causes intracellular signal transduction. There is no enzymatic activity in the β and Υ chains, and specific peptide sequences (immunoreceptor tyros ine-based activation mo) based on two tyrosine groups in the intracellular domain, respectively tif (ITAM) or antigen receptor activation motif (ARAM)) The immunoreceptor tyrosine activation motif (ITAM) -mediated signaling is a function of immune cells. It plays a role in relaying signals activated on immune receptors (τ-cell receptors, β-cell receptors and Fc receptors) and platelets on GPVI and FcyRIIa to the next stage kinases (Syk and ZAP-70) in cells (Underhill, DM and Goodridge, HS, Trends Immunol., 28:66 73, 2007).
리간드가 ITAM-함유 수용체에 결합함으로써 발생된 신호는 비수용체 티로신 키나제인 Src 패밀리로부터 단백질을 보충하도록 하는 신호를 전달한다. 이들 키나제는 ITAM 서열 내의 Syk 또는 ZAP-70 상의 SH2 도메인과 상호작용하는 부분의 티로신기를 인산화시킨다. Syk는 Lyn에 의해 티로신 인산화된 γ사술의 ITAM에 SH2 도메인을 통해 견고하게 결합된다. 이 결합에 의해 자기 인산화 및 Lyn에 의한 인산화가 진행되고， Syk의 구조 변화를 일으킴으로써 활성을 증강시킨다고 알려져 있다 (J. Biol. Chan. , Vol.270. P.10498-10502, 1995).  The signal generated by the binding of the ligand to the ITAM-containing receptor carries a signal that allows the protein to be replenished from the Src family of non-receptor tyrosine kinases. These kinases phosphorylate tyrosine groups in portions that interact with the SH2 domain on Syk or ZAP-70 in the ITAM sequence. Syk is firmly bound to Lyn's ITAM in tyrosine phosphorylated γ surgery via the SH2 domain. Self-phosphorylation and phosphorylation by Lyn proceed by this binding, and it is known to enhance activity by causing structural change of Syk (J. Biol. Chan., Vol. 270. P. 10498-10502, 1995).
활성화된 Syk는 어댑터 분자 복합체의 형성이나 효소의 활성화를 유도하고， 포스포리파아제 CY (PLCY ) , MAP 키나제 (MAPK) 등의 많은 수용체가 이용하는 공통 경로에 신호를 전달한다.  Activated Syk induces the formation of adapter molecule complexes or activation of enzymes and transmits signals to common pathways used by many receptors, such as phospholipase CY (PLCY) and MAP kinase (MAPK).
PLCy는 Syk에 의해 티로신 인산화되고， 포스파티딜이노시를 -4,5- 이인산 (PI-4,5-P2)을 디아실글리세를 (DAG)과 이노시를 1，4，5-삼인산 (IP3)으로 가수분해한다. DAG는 프로테인 키나제 C(PKC)의 활성화를 유도하고， PKC의 활성화는 세포내 칼슘 농도의 상승과 맞물려 탈—과립을 유도한다. 또한， Syk는 키나제 활성을 갖지 않고 SH2 도메인만을 갖고 있는 많은 어댑터 분자와 회합하여 MAPK 수퍼 패밀리를 활성화하고, PLA2의 인산화를 거쳐 아라퀴돈산 대를 야기시킨다. ERK, p38, JNK 등의 활성화는 API 등의 전사 인자를 통해 비만 세포의 사이토카인 생산에 관련되어 있다 (J. Biol. Chew. , Vol.270, p.16333-16338, 1995).  PLCy is tyrosine phosphorylated by Syk, phosphatidylinosyl -4,5-diphosphate (PI-4,5-P2), diacylglycerol (DAG) and inosyl 1,4,5-triphosphate (IP3) Hydrolyze with DAG induces activation of protein kinase C (PKC), which induces de-granulation in combination with elevated intracellular calcium concentrations. In addition, Syk associates with many adapter molecules that do not have kinase activity and only have an SH2 domain to activate the MAPK superfamily, resulting in arachidonic acid bands via phosphorylation of PLA2. Activation of ERK, p38, JNK, etc. is involved in cytokine production of mast cells through transcription factors such as API (J. Biol. Chew., Vol. 270, p. 16333-16338, 1995).
ITAM-매개 신호전달 기능장애로 발생할 수 있는 질환에는, 자가면역 질환, 예컨대， 류마티스 관절염, 루푸스， 다발성 경화증, 용혈성 빈혈, 면역- 혈소관감소증 자반증 및 헤파린 -유도 혈소판감소증 및 동맥경화증이 포함된다. 상기 질환 중 다수는 염증 반응에서 역할을 하는 비만세포， 호염기성 세포 및 다른 면역 세포의 일련의 신호전달을 syk를 통해 활성화시키는 항체에 의한 Fc 수용체를 통해 발생하는 것으로 생각 된다. 자가면역 질환의 하나인 류마티스 관절염 (RA)은 전체 인구의 약 1%에 영향을 미치는 것으로 알려져 있으며， 뼈 및 연골의 파괴를 초래하는 관절부위의 염증을 특징으로 한다. 가역적으로 B 세포 고갈을 야기시키는 리툭시맙 (Rituximab)을 사용한 최근의 임상 실험 결과에 따르면 (J.C.W. Edwards et al 2004， New Eng. J. Med. 350： 2571-2581), B 세포 기능을 표적화하는 것이 RA와 같은 자가면역 질병에서 적절한 치료 전략인 것으로 밝혀졌다. 임상적 효과는 자가반응 항체 (또는 류마티스 인자)의 감소와 관련되고， 이러한 실험은 B 세포 기능 및 사실상 자가항체 생성이 질병의 진행중인 병상에 중추적임을 암시한다. 비장 티로신 키나제 (Syk)가 부족한 마우스로부터의 세포를 사용한 실험은 B 세포 기능에서 이러한 키나제의 비중복적 역할을 입증하였다. Syk의 부족은 B 세포 발달을 차단한다 (M. Turner et al. , 1995, Nature. , 379： 298-302 및 Cheng et al 1995， Nature. , 378： 303-306) . 이들 실험은 Syk가 부족한 성숙된 B 세포에 대한 실험 (Kurasaki et al 2000, Immunol. Rev. , 176: 19-29)과 함께 Syk가 B 세포의 분화 및 활성화를 위해 필요함을 입증한다. 따라서， RA 환자에서 Syk를 억제하는 것은 B 세포 기능을 차단함으로써 류마티스 인자 생산을 감소시키는 것으로 여겨진다. B 세포 기능에서의 Syk의 역할 이외에， RA의 치료와 추가로 관련되는 것은 Fc 수용체 (FcR) 신호전달에서 Syk 활성을 위한 요건이다. RA에서 면역 복합체에 의한 FcR 활성화는 다수의 염증촉진 매개체의 방출에 기여하는 것으로 암시되어 왔다. Diseases that can arise with ITAM-mediated signaling dysfunction include autoimmune diseases such as rheumatoid arthritis, lupus, multiple sclerosis, hemolytic anemia, immune-thrombocytopenic purpura and heparin-induced thrombocytopenia and arteriosclerosis. Many of these diseases cause Fc receptors by antibodies that activate through syk a series of signaling of mast cells, basophils and other immune cells that play a role in the inflammatory response. It is thought to occur through. Rheumatoid arthritis (RA), one of the autoimmune diseases, is known to affect about 1% of the total population and is characterized by inflammation of the joints causing the destruction of bone and cartilage. Recent clinical trials using Rituximab, which reversibly causes B cell depletion (JCW Edwards et al 2004, New Eng. J. Med. 350: 2571-2581), target B cell function. Has been found to be an appropriate treatment strategy in autoimmune diseases such as RA. Clinical effects are associated with a decrease in autoreactive antibodies (or rheumatoid factors), and these experiments suggest that B cell function and in fact autoantibody production are central to the ongoing pathology of the disease. Experiments with cells from mice lacking spleen tyrosine kinase (Syk) demonstrated a nonredundant role of this kinase in B cell function. Lack of Syk blocks B cell development (M. Turner et al., 1995, Nature., 379: 298-302 and Cheng et al 1995, Nature., 378: 303-306). These experiments, along with experiments on mature B cells lacking Syk (Kurasaki et al 2000, Immunol. Rev., 176: 19-29), demonstrate that Syk is required for the differentiation and activation of B cells. Thus, inhibiting Syk in RA patients is believed to reduce rheumatic factor production by blocking B cell function. In addition to the role of Syk in B cell function, further relevant to the treatment of RA is a requirement for Syk activity in Fc receptor (FcR) signaling. FcR activation by immune complexes in RA has been suggested to contribute to the release of a number of proinflammatory mediators.
Syk 키나제 활성의 억제제의 개발은 부적절한 Syk 활성과 관련된 장애의 치료 특히 Syk에 의해 매개되는 질병 치료 및 예방에서 잠재적 치료 이익을 지닌다. 이러한 질환의 예에는 염증 알레르기 및 자가면역 질병， 예를 들어 천식, 만성폐쇄폐질환 (C0PD), 성인 호흡곤란 증후군 (ARDS), 궤양 결장염， 크론병， 기관지염， 피부염， 알레르기성 비염， 건선， 피부경화증， 두드러기， 류마티스 관절염， 다발성 경화증， 암， HIV 및 루푸스를 포함한다. 또한， 췌장， 간장 등을 포함한 각종 암 질환 치료에도 유용하게 이용될 수 있다. The development of inhibitors of Syk kinase activity has potential therapeutic benefits in the treatment of disorders associated with inappropriate Syk activity, in particular in the treatment and prevention of diseases mediated by Syk. Examples of such diseases include inflammatory allergies and autoimmune diseases such as asthma, chronic obstructive pulmonary disease (C0PD), adult respiratory distress syndrome (ARDS), ulcerative colitis, Crohn's disease, bronchitis, dermatitis, allergic rhinitis, psoriasis, skin Sclerosis, urticaria, rheumatoid arthritis, multiple sclerosis, cancer, HIV and lupus. Also, pancreas, liver, etc. It can also be usefully used to treat various cancer diseases, including.
이에 본 발명자들은, Syk 키나제에 대한 우수한 억제 효과를 갖는 신규한 아미노퀴나졸린 화합물올 발견함으로써 본 발명을 완성하였다. 발명의 요약 본 발명의 목적은, 단백질 키나제에 대해 우수한 억제 효과를 갖는 신규한 아미노퀴나졸린 유도체를 제공하는 것이다ᅳ  The present inventors completed the present invention by discovering a novel aminoquinazoline compound having an excellent inhibitory effect on Syk kinase. SUMMARY OF THE INVENTION An object of the present invention is to provide novel aminoquinazoline derivatives having excellent inhibitory effects on protein kinases.
본 발명의 다른 목적은， 상기 아미노퀴나졸린 유도체를 유효성분으로 포함하는 약학 조성물을 제공하는 것이다.  Another object of the present invention is to provide a pharmaceutical composition comprising the aminoquinazoline derivative as an active ingredient.
본 발명의 또 다른 목적은, 상기 아미노퀴나졸린 유도체의 단백질 키나제에 의해 유도된 비정상적인 세포 반웅과 관련된 질환의 예방 또는 치료용 용도를 제공하는 것이다.  Another object of the present invention is to provide a use for the prevention or treatment of a disease associated with abnormal cell reaction induced by the protein kinase of the aminoquinazoline derivative.
본 발명의 또 다른 목적은， 상기 아미노쥐나졸린 유도체의 유효량을 이를 필요로 하는 포유동물에게 투여하는 것을 포함하는, 단백질 키나제에 의해 유도된 비정상적인 세포 반웅과 관련된 질환의 예방 또는 치료방법을 제공하는 것이다. 상기 목적에 따라 본 발명은, 하기 화학식 (I)의 화합물， 및 약제학적으로 허용가능한 그의 염， 이성질체， 수화물 및 용매화물로 이루어진 군에서 선택되는 화합물을 제공한다:  Still another object of the present invention is to provide a method for preventing or treating a disease associated with abnormal cell reaction induced by protein kinase, comprising administering an effective amount of the aminozunazoline derivative to a mammal in need thereof. . According to the above object, the present invention provides a compound selected from the group consisting of a compound of formula (I) and a pharmaceutically acceptable salt, isomer, hydrate and solvate thereof:
Figure imgf000006_0001
Figure imgf000006_0001
상기 식에서,  Where
W, X 및 Y는 각각 득립적으로 C, N, 0또는 S이고， 이때 W, X 및 Y중 하나 이상이 N인 경우 방향족 화합물을 구성할 수 있고, W, X 및 Y가 각각 C 또는 N인 경우， 치환기 R3을 가질 수 있고; o oW, X and Y are each independently C, N, 0 or S, wherein at least one of W, X and Y is N, and may constitute an aromatic compound, and W, X and Y are each C or N sign In the case, may have a substituent R 3; oo
A는 수소， 할로겐, 아미노카르보닐， 카르보닐아미노, _Cᅳ으 , -0-C- , -0- , 아미노， 우레아， 설포닐, 설폭시， 아미노설포닐 및 설포닐아미노로 이루어진 군에서 선택되고; A is selected from the group consisting of hydrogen, halogen, aminocarbonyl, carbonylamino, _C ᅳ, -0-C-, -0-, amino, urea, sulfonyl, sulfoxy, aminosulfonyl and sulfonylamino ;
B는 수소, d-5 알킬， C2-6 알켄일, C5-12 아릴， C5-13 헤테로아릴 C3-13 사이클로알킬 또는 C3-13 헤테로사이클로알킬이며， 여기에서 알킬, 알켄일， 아릴， 헤테로아릴, 사이클로알킬 및 헤테로사이클로알킬은 할로겐, d-5 알킬， 할로 d-5 알킬， c3-8사이클로알킬， 하이드록시， cs—12아릴， c:-5알콕시 , α 5알콕시 )카르보닐, 카르복실, 아미노, 5 알킬)아미노， 피페리딘일, (d-5 알콕시) d-5 알킬， 모르포린일， 아미노카르보닐， 모르포린일 (d-5 알킬), (C!-5 알킬)피페리딘일 , 5 알콕시 )카르보닐피페리딘일， 하이드록시 (CHS 알킬 ) , 하이드록시 (C -5 알콕시 )， (C3ᅳ 8 사이클로알킬 ) (d-5 알콕시), CG-12 아릴옥시， 할로 (d-5 알킬 ) 및 할로 (C6-12 아릴 )로 이루어진 군에서 선택되는 하나 이상의 치환기로 치환될 수 있고， (단， A가 수소 또는 할로겐인 경우 B는 존재하지 않으며); B is hydrogen, d- 5 alkyl, C 2-6 alkenyl, C 5 - 12 aryl, C 5 - 13 heteroaryl, C 3 - 13 cycloalkyl or C 3 - 13, and heterocycloalkyl, where the alkyl, alkenyl , Aryl, heteroaryl, cycloalkyl and heterocycloalkyl are halogen, d- 5 alkyl, halo d- 5 alkyl, c 3-8 cycloalkyl, hydroxy, c s — 12 aryl, c: -5 alkoxy, α 5 Alkoxy) carbonyl, carboxyl, amino, 5 alkyl) amino, piperidinyl, (d- 5 alkoxy) d- 5 alkyl, morpholinyl, aminocarbonyl, morpholinyl (d- 5 alkyl), (C ! 5 Alkyl) piperidinyl, 5 alkoxy) carbonylpiperidinyl, hydroxy (CHS alkyl), hydroxy (C-5 alkoxy), (C 3 ᅳ 8 cycloalkyl) (d- 5 alkoxy), C G - 12 aryloxy, halo (d- 5 alkyl) and halo (C 6 - 12 aryl) as may be substituted by one or more substituents selected from the group consisting of and, (where, a can B is absent when it is bovine or halogen;
Rl, R2 및 R3는 각각 독립적으로 수소， 할로겐, 하이드록시， 아미노， d-5 알킬， (：2-6 알켄일， 알콕시， C1-5아미노, 아미노카보닐， 카보닐아미노， 설포닐, C5-12 아릴， c5-12 해테로아릴， C5-12 바이사이클로아릴， C5-]2 바이사이클로헤테로아릴, C3-12 사이클로알킬 또는 c3-12 헤테로사이클로알킬이며, 여기에서， 알킬, 알켄일， 알콕시， 아미노， 아미노카보닐， 카보닐아미노， 설포닐， 아릴， 헤테로아릴, 바이사이클로아릴， 바이사이클로헤테로아릴， 사이클로알킬 및 해테로사이클로알킬은 할로겐, 하이드록시， 아미노， d-5알킬， 알콕시， d-5아민， 설포닐， c5_12 아릴, C5-12 해테로아릴， C5-12 바이사이클로아릴， c5-12 바이사이클로헤테로아릴， C3-12사이클로알킬 및 C3-12헤테로사이클로알킬로 이루어진 군에서 선택되는 하나 이상의 치환기로 치환될 수 있다. Rl, R2 and R3 are each independently hydrogen, halogen, hydroxy, amino, d- 5 alkyl, (: 2 - 6 alkenyl, alkoxyalkyl, C 1-5 amino, aminocarbonyl, carbonyl, amino, sulfonyl, C 5 - 12 aryl, 5-12 c by interrogating aryl, C 5 - 12 bicyclo aryl, C 5 -] 2 bicyclo heteroaryl, C 3 - 12 cycloalkyl or 3-12 membered heterocycloalkyl c, where , Alkyl, alkenyl, alkoxy, amino, aminocarbonyl, carbonylamino, sulfonyl, aryl, heteroaryl, bicycloaryl, bicycloheteroaryl, cycloalkyl and heterocycloalkyl are halogen, hydroxy, amino, d- 5 alkyl, alkoxy, d-5 amine, sulfonyl, c 5 _ 12 aryl, C 5 - to 12 for interrogating aryl, C 5 - 12 bicyclo aryl, c bicyclo 5-12 heteroaryl, C 3-12 the group consisting of heterocycloalkyl 12 -cycloalkyl and C 3 With one or more substituents selected may be substituted.
상기 다른 목적에 따라 본 발명은, 상기 화학식 (I)의 화합물을 유효성분으로 포함하는， 약학조성물을 제공한다. According to another object of the present invention, the compound of formula (I) Provided as an active ingredient, pharmaceutical composition.
상기 또 다른 목적에 따라 본 발명은， 상기 화학식 (I)의 화합물의 단백질 키나제에 의해 유도된 비정상적인 세포 반웅과 관련된 질환의 예방 또는 치료용 용도를 제공한다.  According to this another object, the present invention provides a use for the prevention or treatment of a disease associated with abnormal cell reaction induced by the protein kinase of the compound of formula (I).
상기 또 다른 목적에 따라 본 발명은， 상기 화학식 (I)의 화합물의 유효량을 이를 필요로 하는 포유동물에게 투여하는 것을 포함하는， 단백질 키나제에 의해 유도된 비정상적인 세포 반응과 관련된 질환의 예방 또는 치료방법을 제공한다. 발명의 상세한설명 본 발명의 한 실시양태에 따르면， 본원 발명의 화학식 (I)의 화합물은， 하기 화학식 (i-a)의 화합물로 표시될 수 있다: According to another object of the present invention, the present invention provides a method for preventing or treating a disease associated with abnormal cell response induced by protein kinase, comprising administering to a mammal in need thereof an effective amount of the compound of formula (I). To provide. DETAILED DESCRIPTION OF THE INVENTION According to one embodiment of the invention, the compound of formula (I) of the present invention may be represented by a compound of formula (i- a ):
Figure imgf000008_0001
상기 식에서，
Figure imgf000008_0001
In the above formula,
D는 C 또는 N이고;  D is C or N;
Rl, R2 및 R3은 각각 독립적으로 수소， 할로겐， 하이드록시， 아미노， C1-5 알킬， C2-S 알켄일, CHS알콕시 , d-5 아미노， 아미노카보닐， 카보닐아미노， 설포닐，R 1, R 2 and R 3 are each independently hydrogen, halogen, hydroxy, amino, C 1-5 alkyl, C 2 -S alkenyl, CHSalkoxy, d- 5 amino, aminocarbonyl, carbonylamino, sulfonyl,
C5-12아릴， C5_12바이사이클로아릴, C5-12바이사이클로헤테로아릴, C3-12사이클로알킬 또는 C3-12 헤테로사이클로알킬이고, 여기에서, 알킬， 알켄일, 알콕시， 아미노， 아미노카보닐， 카보닐아미노, 설포닐， 아릴， 바이사이클로아릴， 바이사이클로헤테로아릴， 사이클로알킬 및 헤테로사이클로알킬은 할로겐， 하이드록시， 아미노， 알킬， C2-6 알켄일, d-5 알콕시, d-5 아민, 설포닐, C5-]2 아릴， C5-12 헤테로아릴， C5-]2 바이사이클로아릴, C5-12바이사이클로헤테로아릴， C3-12 사이클로알킬 및 c3-12헤테로사이클로알킬로 이루어진 군에서 선택되는 하나 이상의 치환기로 치환될 수 있고; C 5 - 12 aryl, C 5 _ 12 bicyclo aryl, C 5 - 12 bicyclo heteroaryl, C 3 - 12 cycloalkyl or C 3 - 12, and heterocycloalkyl, where the alkyl, alkenyl, alkoxy, amino , aminocarbonyl, carbonyl, amino, sulfonyl, aryl, bicyclo aryl, bicyclo heteroaryl, cycloalkyl, and heterocycloalkyl, halogen, hydroxy, amino, alkyl, C 2 - 6 alkenyl, d- 5 alkoxy , d- 5 amine, sulfonyl, C 5- ] 2 Aryl, C 5 - 12 heteroaryl, C 5 -] 2 bicyclo aryl, C 5 - 12 bicyclo heteroaryl, C 3 - 12 cycloalkyl, and c 3-12 heterocycloalkyl one or more substituents selected from the group consisting of alkyl May be substituted with;
R4 및 R5는 각각 독립적으로 수소， d-5알킬， d-5알킬아미노， C2-6알켄일， C5-12아릴， C5-12바이사이클로아릴， C5—12바이사이클로헤테로아릴， C3-12사이클로알킬 또는 C3-12 헤테로사이클로알킬이고， 여기에서, 알킬, 알킬아미노， 알켄일， 아릴， 바이사이클로아릴， 바이사이클로헤테로아릴, 사이클로알킬 및 헤테로사이클로알킬은 하이드록시， 아미노， 알킬아민， 알킬 , C2-6알켄일， C5-R4 and R5 are each independently hydrogen, d- 5 alkyl, d- 5 alkylamino, C 2 - 6 alkenyl, C 5 - 12 aryl, C 5 - 12 bicyclo aryl, C 5 - 12 bicyclo heteroaryl, C 3 - 12 cycloalkyl or C 3 - and 12 heterocycloalkyl, where the alkyl, amino, alkenyl, aryl, bicyclo aryl, bicyclo heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with hydroxy, amino, alkyl amines, alkyl, C 2 - 6 alkenyl, C 5 -
12아릴， C5-12바이사이클로아릴， C5-12바이사이클로헤테로아릴， C3-12사이클로알킬 및 c3-i2헤테로사이클로알킬로 이루어진 군에서 선택되는 하나 이상의 치환기로 치환될 수 있고; 12 aryl, C 5 - 12 bicyclo aryl, C 5 - 12 bicyclo heteroaryl, C 3 - 12 cycloalkyl, and c 3 - i2 heterocycloalkyl may be substituted with one or more substituents selected from the group consisting of alkyl and;
이때， R4 및 R5는 서로 연결되어 HJ카보사이클， C2-6 헤테로사이클， C5-12 바이사이클 또는 C5-12헤테로바이사이클을 형성할 수 있으며， 여기에서 카보사이클， 헤테로사이클， 바이사이클 및 헤테로바이사이클은 할로겐， 하이드톡시， 아미노, 알킬아민, d-5 알킬， C2-6 알켄일， C5-12 아릴, C5-12 바이사이클로아릴， C5-12 바이사이클로해테로아릴, C3-12사이클로알킬 및 C3-12헤테로사이클로알킬로 이루어진 군에서 선택되는 하나 이상의 치환기로 치환될 수 있고; In this case, R4 and R5 are connected to each other HJ carbocycle, C 2 - 6 heterocyclyl, C 5 - 12 by-cycle or a C 5 - 12 may form a hetero-by-cycle, carbocycle Here, heterocycle, by-cycle and heteroaryl-by-cycle is halogen, hydroxy ethoxy, amino, alkylamine, d- 5 alkyl, C 2 - 6 alkenyl, C 5 - 12 aryl, C 5 - 12 bicyclo aryl, C 5 - 12 aryl bicyclo by Tero , C 3-12 cycloalkyl, and C 3 - and may be substituted with one or more substituents selected from the group consisting of 12-heterocycloalkyl;
이때 R4 및 R5가 C2-6 해테로사이클 또는 C5-12 헤테로바이사이클인 경우， 헤테로 원소는 0， N, S, S=0 및 S02로 이루어진 군에서 선택되며, 헤테로 원소가 N인 경우 치환기 R6으로 치환될 수 있고, 이때, R6는 수소， d-3저급 알킬 또는 C3-6 사이클로알킬이고， 여기에서 저급 알킬 또는 사이클로 알킬은 하나 이상의 할로겐으로 치환될 수 있다. 상기 화학식 (I-a)의 화합물에서 바람직한 화합물은， D가 질소인 하기 화학식 Π-a' )의 화합물로 표시될 수 있다: R2011/007194 Wherein R4 and R5 are C 2 - 6 by interrogating cycle or C 5 - For the 12 hetero-by-cycle, a hetero element is selected from the group consisting of 0, N, S, S = 0 and S0 2, the hetero element is N case can be optionally substituted with substituents R6, wherein, R6 is hydrogen, d- 3 lower alkyl or C 3 - 6 may be substituted with cycloalkyl, lower alkyl or cycloalkyl substituted by one or more halogens here. Preferred compounds in the compounds of formula (Ia) may be represented by compounds of formula (Π-a ') wherein D is nitrogen: R2011 / 007194
Figure imgf000010_0001
상기 식에서 ,
Figure imgf000010_0001
Where
R1은 수소; 할로겐, 예를 들어 클로로 또는 플루오로; 및 하나 이상의 할로겐으로 임의로 치환된 d-5알킬 및 알콕시로 이루어진 군에서 선택되고， 예를 들어, 상기 C!-5 알킬은 메틸， 에틸 또는 이소프로필이고， 상기 d-5 알콕시는 메톡시， 에특시 또는 이소프로폭시이며， 할로겐으로 치환된 C1-5 알킬은 CF3이고, 할로겐으로 치환된 알콕시는 -0CF3이다. R 1 is hydrogen; Halogen, for example chloro or fluoro; And d- 5 alkyl and alkoxy optionally substituted with one or more halogens. For example, C ! 5 alkyl is methyl, ethyl or isopropyl, the d- 5 alkoxy is methoxy, epoxy or isopropoxy, halogen substituted C 1-5 alkyl is CF 3 , halogen substituted alkoxy is 0CF 3 .
R2는 수소; 할로겐; 및 하나 이상의 할로겐으로 임의로 치환된, d-5 알킬， C1-5알콕시， ( 5아미노 및 C3-6사이클로알콕시로 이루어진 군에서 선택되며 ; R2 is hydrogen; halogen; And optionally substituted by one or more halogen, d- 5 alkyl, C 1-5 alkoxy, (5-amino and C 3 - 6 are each individually selected from the group consisting of cycloalkoxy;
R3은 수소; 및 하나 이상의 할로겐으로 임의로 치환된， d-5 알킬 및 C3-12 사이클로알킬로 이루어진 군에서 선택되며 , 예를 들어， ( 5알킬은 메틸， 에틸 또는 이소프로필이고, 상기 ¾-12사이클로알킬은 사이클로프로필 또는 사이클로부틸이다. R3 is hydrogen; And optionally substituted by one or more halogen, d-5 alkyl and C 3 - 12 are each individually selected from the group consisting of cycloalkyl, e.g., (5-alkyl is methyl, ethyl or isopropyl, the ¾- 12 cycloalkyl Cyclopropyl or cyclobutyl.
R4 및 R5는 각각 독립적으로 수소; 및 할로겐， 하이드록시, 아미노， 모폴린, 피페리딘， 피페라진, 알킬피페라진 및 C3H5사이클로알킬피페라진으로 이루어진 군에서 선택되는 하나 이상의 치환기로 임의로 치환된， ( 5알킬 , d-5알킬아미노 , C2-6 알켄일, C5-12아릴， C5-12바이사이클로아릴 , C5-12바이사이클로해테로아릴， C3_12 사이클로알킬 및 -12헤테로사이클로알킬로 이루어진 군에서 선택되며; R4 and R5 are each independently hydrogen; And optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, morpholine, piperidine, piperazine, alkylpiperazine and C 3 H 5 cycloalkylpiperazine ( 5 alkyl, d- 5 alkyl amino, C 2 - 6 alkenyl, C 5 - 12 aryl, C 5 - 12 bicyclo aryl, C 5 - 12 bicyclo by interrogating aryl, C 3 _ 12 cycloalkyl, and 12 selected from the group consisting of heterocycloalkyl Become;
이때， R4 및 R5는 서로 연결되어 사이클을 형성할 수 있으며, 상기 사이클은 N, 0 및 S로 이루어진 군에서 선랙된 하나 이상의 해테로 원소를 포함할 수 있으며, 상기 헤테로 원소가 N인 경우 치환기 R6으로 치환될 수 있고， 이때， R6은 수소; 및 하나 이상의 할로겐, 바람직하게는 클로로 또는 플루오로로 임의로 치환된， ( 5 알킬, C3-12 사이클로알킬 및 C3-12 사이클로알킬 -C1-5 알킬로 이루어진 군에서 선택될 수 있으며， 예를 들어, 상기 알킬은 메틸， 에틸 또는 이소프로필이고, 상기 c3-12 사이클로알킬은 사이클로프로필이며， 상기 C3-12 사이클로알킬 -C-5알킬은 사이클로프로필메틸이다. 본 발명의 한 실시양태에 따르면， 본원 발명의 화학식 (I)의 화합물은， 하기 화학식 (I-b)의 화합물로 표시될 수 있다: In this case, R4 and R5 may be connected to each other to form a cycle, the cycle may include one or more heteroatoms selected from the group consisting of N, 0 and S, when the hetero element is N substituent R6 It may be substituted with, wherein R6 is hydrogen; And in with one or more halogen, preferably chloro or fluoro, optionally substituted, (5 alkyl, C 3 - 12 cycloalkyl, and C 3 - 12 cycloalkyl, and it may be selected from the group consisting of -C 1-5 alkyl, such as For example, the alkyl may be methyl, ethyl or And isopropyl, wherein c 3-12 cycloalkyl is cyclopropyl, the C 3 - 12 cycloalkyl, -C- 5 alkyl is cyclopropylmethyl. According to one embodiment of the invention, the compound of formula (I) of the present invention may be represented by a compound of formula (Ib):
Figure imgf000011_0001
Figure imgf000011_0001
상기 식에서，  In the above formula,
X는 C 또는 N이고;  X is C or N;
R1은 수소; 할로겐, 예를 들어 클로로 또는 플루오로; 및 하나 이상의 할로겐으로 임의로 치환된， d-5 알킬 및 d-5알콕시로 이루어진 군에서 선택되고， 예를 들어 , 상기 ( 5 알킬은 메틸, 에틸 또는 이소프로필이고, 상기 d-5 알콕시는 메톡시， 에톡시 또는 이소프로폭시이며 , 할로겐으로 치환된 C1-5 알킬은 CF3이고， 할로겐으로 치환된 d-5알콕시는 -0CF3이다. R 1 is hydrogen; Halogen, for example chloro or fluoro; And d- 5 alkyl and d- 5 alkoxy, optionally substituted with one or more halogens, for example, wherein ( 5 alkyl is methyl, ethyl or isopropyl, and d- 5 alkoxy is methoxy , Ethoxy or isopropoxy, halogen substituted C 1-5 alkyl is CF 3 and halogen substituted d- 5 alkoxy is —0CF 3 .
R2는 수소; 할로겐; 및 하나 이상의 할로겐으로 임의로 치환된， C-5알킬，R2 is hydrogen; halogen; And C- 5 alkyl optionally substituted with one or more halogens.
CH;알콕시， ( 5아미노 및 C3-6사이클로알콕시로 이루어진 군에서 선택되며; CH; alkoxy, (5-amino and C 3 - 6 are each individually selected from the group consisting of cycloalkoxy;
R3은 수소; 및 하나 이상의 할로겐으로 임의로 치환된， d-5 알킬 및 C3-12 사이클로알킬로 이루어진 군에서 선택되며， 예를 들어， 상기 C 5알킬은 메틸, 에틸 또는 이소프로필이고, 상기 C3-12 사이클로알킬은 사이클로프로필 또는 사이클로부틸이다. R3 is hydrogen; And optionally substituted by one or more halogen, d- 5 alkyl, C 3 - is selected from the group consisting of 12-cycloalkyl, for example, the C 5 alkyl is methyl, ethyl or isopropyl, the C 3 - 12 cycloalkyl Alkyl is cyclopropyl or cyclobutyl.
R4 및 R5는 각각 독립적으로 수소; 및 할로겐, 하이드록시， 아미노, 모폴린， 피페리딘， 피페라진， d-6알킬피페라진 및 C3-6사이클로알킬피페라진으로 이루어진 군에서 선택되는 하나 이상의 치환기로 임의로 치환된， d-5알킬， d-5알킬아미노, C2-6 알켄일， C5—12 아릴， C5-12 바이사이클로아릴， C5-12바이사이클로해테로아릴, C3-12 사이클로알킬 및 c3ᅳ 12해테로사이클로알킬로 이루어진 군에서 선택되며; R4 and R5 are each independently hydrogen; And halogen, hydroxy, amino, morpholine, piperidine, piperazine, d- 6 alkyl piperazine and C 3 - 6 cycloalkyl piperazine optionally with one or more substituents selected from the group consisting of a substituted, 5 d- Alkyl ， d- 5 alkylamino, C 2 - 6 alkenyl, C 5 - 12 aryl, C 5-12 bicyclo aryl, C 5 - 12 bicyclo by interrogating aryl, C 3 - 12 cycloalkyl, and c 3 to 12 eu from the group consisting of cycloalkyl, Tero Selected;
이때， R4 및 R5는 서로 연결되어 사이클을 형성할 수 있으며, 상기 사이클은 N, 0 및 S로 이루어진 군에서 선택된 하나 이상의 해테로 원소를 포함할 수 있으며， 상기 헤테로 원소가 N인 경우 치환기 R6으로 치환될 수 있고， 이때， R6은 수소; 및 하나 이상의 할로겐， 바람직하게는 클로로 또는 플루오로로 임의로 치환된， d-5 알킬, C3-12 사이클로알킬 및 C3-12 사이클로알킬 -d-5 알킬로 이루어진 군에서 선택될 수 있으며， 예를 들어， 상기 d-5 알킬은 메틸 에틸 또는 이소프로필이고， 상기 C3-I2 사이클로알킬은 사이클로프로필이며， 상기 C3-12 사이클로알킬 -d-5알킬은사이클로프로필메틸이다. 본 발명의 한 실시양태에 따르면, 본원 발명의 화학식 (I)의 화합물은， 하기 화학식 (I-c)의 화합물로 표시될 수 있다: In this case, R4 and R5 may be connected to each other to form a cycle, the cycle may include one or more hetero elements selected from the group consisting of N, 0 and S, when the hetero element is N to substituent R6 Which may be substituted, wherein R6 is hydrogen; And at least one halogen, preferably optionally substituted with chloro or fluoro, d- 5 alkyl, C 3 - 12 cycloalkyl, and C 3 - 12 may be selected from the group consisting of cycloalkyl, -d- 5 alkyl, such as for example, the d- 5 alkyl is methyl ethyl or isopropyl, the C 3 - I2 cycloalkyl is cyclopropyl, the C 3 - 12 cycloalkyl, -d- 5 alkyl is cyclopropylmethyl. According to one embodiment of the invention, the compound of formula (I) of the present invention may be represented by a compound of formula (Ic):
Figure imgf000012_0001
상기 식에서,
Figure imgf000012_0001
Where
R1은 수소; 할로겐, 예를 들어 클로로 또는 플루오로; 및 하나 이상의 할로겐으로 임의로 치환된， d-5 알킬 및 d-5 알콕시로 이루어진 군에서 선택되고， 예를 들어， 상기 ( 5 알킬은 메틸, 에틸 또는 이소프로필이고， 상기 d-5 알콕시는 메톡시， 에톡시 또는 이소프로폭시이며， 할로겐으로 치환된 d-5 알킬은 CF3이고， 할로겐으로 치환된 C1-5알콕시는 -0CF3이다. R 1 is hydrogen; Halogen, for example chloro or fluoro; And d- 5 alkyl and d- 5 alkoxy, optionally substituted with one or more halogens, for example, wherein ( 5 alkyl is methyl, ethyl or isopropyl, and d- 5 alkoxy is methoxy , Ethoxy or isopropoxy, halogen substituted d- 5 alkyl is CF 3 and halogen substituted C 1-5 alkoxy is -0CF 3 .
R2는 수소; 할로겐， 예를 들어 클로로 또는 플루오로; 및 하나 이상의 할로겐으로 임의로 치환된, 알콕시 및 C3-6사이클로알콕시로 이루어진 군에서 선택되고; R2 is hydrogen; Halogen, for example chloro or fluoro; And optionally substituted by one or more halogen, alkoxy and C 3 - 6 from a group consisting of cycloalkoxy Selected;
R3은 수소; 및 하나 이상의 할로겐으로 임의로 치환된， d-5 알킬 및 C3-12 사이클로알킬로 이루어진 군에서 선택되고， 예를 들어， 상기 d-5알킬은 메틸, 에틸 또는 이소프로필이고， 상기 C3_12 사이클로알킬은 사이클로프로필 또는 사이클로부틸이다. R3 is hydrogen; And d- 5 alkyl and C 3-12 cycloalkyl, optionally substituted with one or more halogens, for example, the d- 5 alkyl is methyl, ethyl or isopropyl, and C 3 _ 12 Cycloalkyl is cyclopropyl or cyclobutyl.
R7 및 R8은 각각 독립적으로 수소; 및 하나 이상의 할로겐으로 임의로 치환된， 알킬 및 -12사이클로알킬로 이루어진 군에서 선택되고, 예를 들어， 상기 d-5 알킬은 메틸， 에틸 또는 이소프로필이고, 상기 C3-12 사이클로알킬은 사이클로프로필 또는 사이클로부틸이다. R7 and R8 are each independently hydrogen; And alkyl and -12 cycloalkyl, optionally substituted with one or more halogens, for example, the d- 5 alkyl is methyl, ethyl or isopropyl, and the C 3-12 cycloalkyl is cyclopropyl Or cyclobutyl.
Z는 공유결합， -CHR6, -0-， -NR6- 및 -S02-로 이루어진 군에서 선택되고; 이때， 상기 R6은 하나 이상의 할로겐, 예를 들에 클로로 또는 플루오로로 임의로 치환된， C-5 알킬， C3-12 사이클로알킬 및 C3-12 사이클로알킬 -d-5 알킬로 이루어진 군에서 선택되고， 예를 들어， 상기 d-5알킬은 메틸， 에틸 또는 이소프로필이고, C3ᅳZ is selected from the group consisting of a covalent bond, -CHR6, -0-, -NR6- and -S0 2- ; In this case, the R6 is an optionally as chloro or fluoro in the at least one halogen, for example, substitution, C- 5 alkyl, C 3 - 12 cycloalkyl, and C 3 - 12 cycloalkyl, -d- selected from the group consisting of alkyl 5 For example, the d- 5 alkyl is methyl, ethyl or isopropyl, C 3 ᅳ
12 사이클로알킬은 사이클로프로필이고， 상기 C3-12 사이클로알킬 -d-5 알킬은 사이클로프로필메틸이다. 본 발명의 한 실시양태에 따르면 , 본원 발명의 화학식 (I)의 화합물은， 하기 화학식 (I-d)의 화합물로 표시될 수 있다:
Figure imgf000013_0001
12 Cycloalkyl is cyclopropyl, a C 3 - 12 cycloalkyl, -d- 5 alkyl is cyclopropylmethyl. According to one embodiment of the invention, the compound of formula (I) of the present invention may be represented by a compound of formula (Id):
Figure imgf000013_0001
상기 식에서,  Where
R1은 수소; 할로겐, 예를 들어 클로로 또는 플루오로; 및 하나 이상의 할로겐으로 임의로 치환된, d-5 알킬 및 d-5 알콕시로 이투어진 군에서 선택되고， 예를 들어, 상기 C1-5 알킬은 메틸， 에틸 또는 이소프로필이고, 상기 d-5 알콕시는 메톡시, 에톡시 또는 이소프로폭시이며, 할로겐으로 치환된 d-5 알킬은 CF3이고， 할로겐으로 치환된 -5알콕시는 -0CF3이다. R2는 수소; 할로겐, 예를 들어 클로로 또는 플루오로; 및 하나 이상의 할로겐으로 임의로 치환된， d-5 알콕시 및 C3-6사이클로알콕시로 이루어진 군에서 선택되고; R 1 is hydrogen; Halogen, for example chloro or fluoro; And d- 5 alkyl and d- 5 alkoxy, optionally substituted with one or more halogens, for example the C 1-5 alkyl is methyl, ethyl or isopropyl, the d- 5 alkoxy Is methoxy, ethoxy or isopropoxy, the d- 5 alkyl substituted with halogen is CF 3 and the -5 alkoxy substituted with halogen is -0CF 3 . R2 is hydrogen; Halogen, for example chloro or fluoro; And optionally substituted by one or more halogen, d- 5 alkoxy and C 3 - 6 is selected from the group consisting of cycloalkoxy;
R3은 수소; 및 할로겐， d-5 알킬， d-5 알콕시 , C3-6 사이클로알콕시， d-6 알킬아미노, -12사이클로알킬， C3-12헤테로사이클로알킬, C5-12아릴 및 C5-12헤테로 아릴로 이루어진 군에서 선택된 하나 이상의 치환기로 임의로 치환된， d-5알킬， - 5 알콕시， C3-6사이클로알콕시， 아미노, d-6 알킬 아미노, -12사이클로알킬， C3-12 헤테로사이클로알킬 , C5-12아릴 및 C5-]2헤테로아릴로 이루어진 군에서 선택된다. 본원에서 사용된 용어 "할로 " 또는 "할로겐"이란， 플루오로, 브로모, 클로로 또는 아이오도를 의미한다. R3 is hydrogen; And halogen, d- 5 alkyl, d- 5 alkoxy, C 3 - 6 cycloalkoxy, d- 6 alkylamino, - 12 cycloalkyl, C 3 - 12 heterocycloalkyl, C 5 - 12 aryl and C 5 - 12 hetero optionally substituted with one or more substituents selected from the group consisting of aryl, 5-d- alkyl, - 5 alkoxy, C 3 - 6 cycloalkoxy, amino, d- 6 alkylamino, - 12 cycloalkyl, C 3 - 12 heterocycloalkyl It is selected from - the group consisting of 2-heteroaryl -, C 5 - 12 aryl and C 5. As used herein, the term "halo" or "halogen" means fluoro, bromo, chloro or iodo.
본원에서 사용된 용어 "알킬 "이란， 선형 또는 분지형의 포화된 C 내지 ¾의 탄화수소 라디칼 사슬을 의미한다. 구체적인 예로는 메틸， 에틸， n-프로필， 이소프로필, n-부틸, 이소부틸， t-부틸， n—펜틸 또는 이소펜틸 등을 들 수 있으나， 이에 한정되지는 않는다.  As used herein, the term "alkyl" refers to a linear or branched saturated C to ¾ hydrocarbon radical chain. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl or isopentyl.
본원에 사용된 용어 "알킨일''이란, 삼중 결합을 갖는 알킨에서 수소 두 개가 빠진 2가의 탄화수소기를 의미한다. 구체적인 예로는 에틴일， 프로핀일 등을 들 수 있으나， 이에 한정되지는 않는다.  As used herein, the term "alkynyl" refers to a divalent hydrocarbon group having two hydrogens removed from an alkyne having a triple bond, and specific examples include, but are not limited to, ethynyl, propynyl, and the like.
본원에서 사용되는 용어 "아릴"은 나프틸， 페난트레닐 등과 같은 융합된 기 뿐만 아니라 페닐, 치환된 페닐 등과 같은 모노사이클릭 또는 비사이클릭 방향족 고리를 포함한다. 구체적인 예로는 페닐， 를루일， 크실일， 비페닐 및 나프틸 등을 들 수 있으나, 이에 한정되는 것은 아니다.  The term "aryl" as used herein includes fused groups such as naphthyl, phenanthrenyl and the like as well as monocyclic or bicyclic aromatic rings such as phenyl, substituted phenyl and the like. Specific examples include, but are not limited to, phenyl, toluyl, xylyl, biphenyl and naphthyl.
본원에서 사용되는 용어 "해테로아릴 "은 산소， 질소 및 황 중에서 선택된 해테로원자를 함유하는 모노사이클릭 또는 바이사이클릭 이상의 방향족 그룹을 의미한다. 모노사이클릭 헤테로아릴의 예로는 퓨릴， 티엔일， 싸이아졸릴, 피라졸릴, 이소싸이아졸릴， 옥사졸릴， 이소옥사졸일， 피를릴， 트라이아졸릴, 테트라졸릴， 이미다졸릴, 노 옥사디아졸릴， 1 2 4_옥사디아졸릴， 1 2 3_옥사디아졸릴， 1， 3, 5-싸이아디아졸릴, 1,2， 3-싸이아디아졸릴， 1， 2, 4-싸이아디아졸릴, 피리딜, 피리미딜, 피라진일， 피리다진일, 1，2，4-트라이아진일, 1，2，3ᅳ트라이아진일, 1,3, 5-트라이아진일， 신놀린일， 프테리딘일, 퓨린일, 6,7-디히드로-511-[1]피리딘일, 바이사이클릭 헤테로아릴의 예로는 이환으로서 5，6，7，8-테트라히드로-퀴놀린 -3-일， 벤조 [d][l,3]디옥솔릴， 벤조옥사졸릴, 벤조싸이아졸릴， 벤조 [b]싸이오펜일， 벤조이소싸이아졸릴, 벤조이소옥사졸일， 벤즈이미다졸릴, 싸이아나프텐일， 이소싸이아나프텐일 벤조퓨란일, 이소벤조퓨란일, 이소인돌릴， 인돌릴, 인돌리진일， 인다졸릴, 이소퀴놀릴 퀴놀릴, 프탈라진일, 퀸옥살린일, 퀴나졸린일， 피라졸로 [3,4-b]피리딘일, 또는 벤조옥사진일 등을 들 수 있으나 이에 한정되지는 않는다. As used herein, the term “heteroaryl” means a monocyclic or bicyclic or higher aromatic group containing a heteroatom selected from oxygen, nitrogen and sulfur. Examples of monocyclic heteroaryls include furyl, thienyl, thiazolyl, pyrazolyl, isoazolyl, oxazolyl, isoxazolyl, pyryl, triazolyl, tetrazolyl, imidazolyl, nooxadia Jolyl, 1 2 4 _oxadiazolyl, 1 2 3 _oxadiazolyl, 1, 3, 5-thiadiazolyl, 1,2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2, 4-triazineyl, 1,2,3 ᅳ triazineyl, 1,3, 5-triazineyl, cinnaline, putridinyl, purinyl, 6,7-dihydro-511- [1] pyridine Examples of one, bicyclic heteroaryl include 5,6,7,8-tetrahydro-quinolin-3-yl, benzo [d] [l, 3] dioxolyl, benzooxazolyl, benzothiazolyl, as bicyclic; Benzo [b] thiophenyl, benzoisothiazolyl, benzoisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl benzofuranyl, isobenzofuranyl, isoindolinyl, indolyl, Indolizinyl, indazolyl, isoquinolyl quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, pyrazolo [3,4-b] pyridinyl, or benzoxazineyl, and the like. Does not.
본원에서 사용되는 용어 "사이클로알킬"이란， 환상알킬을 의미한다. 구체적인 예로는 사이클로프로필, 사이클로부틸， 사이클로핵실 둥을 들 수 있으나， 이에 한정되는 것은 아니다.  The term "cycloalkyl" as used herein, means cyclic alkyl. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, and cyclonuclear cylinders.
본원에서 사용되는 용어 "헤테로사이클로알킬"이란， 산소， 질소 및 황 중에서 선택된 헤테로원자를 함유하는 모노사이클릭 또는 바이사이클릭 이상의 환상 알킬을 나타낸다. 모노 헤테로사이클로알킬의 예로는 피페리딘, 모르포린， 티아모르포린， 피롤리딘, 이미다졸리딘， 테트라히드로퓨란， 피페라진 등을 들 수 있으나， 이에 한정되지는 않는다.  As used herein, the term “heterocycloalkyl” refers to monocyclic or bicyclic or higher cyclic alkyl containing heteroatoms selected from oxygen, nitrogen and sulfur. Examples of mono heterocycloalkyl include, but are not limited to, piperidine, morpholine, thiamorpholine, pyrrolidine, imidazolidine, tetrahydrofuran, piperazine, and the like.
본원에 사용된 용어 "알콕시"란 -0Ra 기를 의미하는 것으로, 여기서 1^는 앞서 정의한 바와 같은 알킬이다. 구체적인 예로는 메록시， 에톡시， n-프로폭시, 이소프로폭시, n-부톡시， t-부톡시 등을 들 수 있으나, 이에 한정되지는 않는다. 본 발명에 따른 바람직한 화합물의 구체예는 하기 표 1에 기재된 화합물들과 같다. [표 1] As used herein, the term "alkoxy" refers to the group -0R a , where 1 ^ is alkyl as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, and the like. Specific examples of the preferred compounds according to the invention are the same as those listed in Table 1 below. TABLE 1
Figure imgf000016_0001
l-(3-다이메틸아미노-프로필 )-3-[2-메
Figure imgf000016_0001
l- (3-dimethylamino-propyl) -3- [2-meth
틸 -6-(8-메틸-퀴나졸린 -2-일아미노) -
Figure imgf000017_0001
Tyl-6- (8-methyl-quinazolin-2-ylamino)-
Figure imgf000017_0001
1H-벤즈이미다졸 -4-일] -우레아 1H-benzimidazol-4-yl] -urea
(2-메틸 -3H-벤즈이미다졸 -5—일 )— (8-메 (2-Methyl-3H-benzimidazole-5-yl) — (8-meth
틸-퀴나졸린 -2-일)ᅳ아민
Figure imgf000017_0002
Tyl-quinazolin-2-yl) ᅳ amine
Figure imgf000017_0002
(7-브로모 -2-메틸 -3H-벤즈이미다졸 -5- 일 )-(8-메틸-퀴나졸린 -2-일 ) -아민
Figure imgf000017_0003
(7-Bromo-2-methyl-3H-benzimidazol-5-yl)-(8-methyl-quinazolin-2-yl) -amine
Figure imgf000017_0003
N-[2-메틸 -6-(8-메틸-퀴나졸린 -2-일아 N- [2-methyl-6- (8-methyl-quinazolin-2-yl
미노) -1H-벤즈이미다졸 -4-일] -4— (4-메
Figure imgf000017_0004
Mino) -1H-benzimidazol-4-yl] -4— (4-meth
Figure imgf000017_0004
틸-피페라진 -1-일 ) -부틸아미드 Tyl-piperazin-1-yl) -butylamide
Br Br
[6-(7-브로모-퀴나졸린 -2—일아미노) - 2-메틸 -1H-벤즈이미다졸 -4-일] -카바민  [6- (7-Bromo-quinazolin-2—ylamino)-2-methyl-1H-benzimidazol-4-yl] -carbamine
산 에틸 에스터 H H Acid Ethyl Ester H H
1-(3-다이메틸아미노-프로필 )-3-[6- (8-메틸―퀴나졸린 -2-일아미노) -1H-인 1- (3-dimethylamino-propyl) -3- [6- (8-methyl-quinazolin-2-ylamino) -1H-phosphorus
다졸 -4-일] -우레아
Figure imgf000017_0005
Br Dozol-4-yl] -urea
Figure imgf000017_0005
Br
N6-(7-브로모-퀴나졸린—2-일 ) -2-메틸- 1H-벤즈이 미다졸 -4， 6-다이 아민 니소 ΝΗ2 N 6- (7-bromo-quinazolin-2-yl) -2-methyl-1H-benzimidazole-4, 6-diamine nisso ΝΗ 2
4-(4-메틸-피페라진 -1-일 ) -N-[6-(8-메 4- (4-Methyl-piperazin-1-yl) -N- [6- (8-meth
틸-퀴나졸린 -2-일아미노) -1H-인다졸-
Figure imgf000018_0001
Tyl-quinazolin-2-ylamino) -1H-indazole-
Figure imgf000018_0001
4-일 ] -부틸아미드 4-yl] -butylamide
(7-브로모-퀴나졸린 -2-일 )-(2-메틸- 3H-벤즈이미다졸 -5-일 ) -아민(7-Bromo-quinazolin-2-yl)-(2-methyl-3H-benzimidazol-5-yl) -amine
Figure imgf000018_0002
Figure imgf000018_0002
2-메틸 -6-(8-메틸-퀴나졸린 -2-일아미 2-methyl-6- (8-methyl-quinazolin-2-ylami
노) -1H-벤즈이 미다졸 -4-카르복시 산 No) -1H-benzimidazole-4-carboxylic acid
o 사이클로프로필아미드  o cyclopropylamide
1-[2-메틸 -6— (8-메틸-퀴나졸린 -2-일아 1- [2-methyl-6— (8-methyl-quinazolin-2-yl
미노) -1H-벤즈이 미다졸 -4-일 ]-3-(2-피 Mino) -1H-benzimidazol-4-yl] -3- (2-p
페 리 딘 -1-일-에틸 ) -우레아Ferridin-1-yl-ethyl) -urea
Figure imgf000018_0003
피 페 리 딘 -1-카르복실산 [2-메틸 -6-(8- 메틸-퀴나졸린 -2-일아미노) -1H-벤즈이
Figure imgf000018_0003
Piperidine-1-carboxylic acid [2-methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzi
미 다졸 _4-일 ]—아미드 H H 2-메틸 -6ᅳ(8-메틸-퀴나졸린 -2-일아미 Midazol _ 4 -yl] —amide HH 2-methyl-6 '(8-methyl-quinazolin-2-ylamimi
노) -1H-벤즈이미다졸 -4-카르복실산 No) -1H-benzimidazole-4-carboxylic acid
(2-피페리딘 -1-일―에틸 ) -아미드 (2-piperidin-1-yl-ethyl) -amide
[2-메틸 -6— (8-메틸-퀴나졸린 -2-일아미 [2-Methyl-6— (8-methyl-quinazolin-2-ylamimi
노) -1H-벤즈이미다졸 -4-일] -메탄올 No) -1H-benzimidazol-4-yl] -methanol
1-(3-다이메틸아미노-프로필) -1—메틸- 3-[2-메틸 -6-(8-메틸-퀴나졸린 -2-일아 1- (3-dimethylamino-propyl) -1-methyl- [3-methyl-2-6- (8-methyl-quinazolin-2-yl)
미노) - 1H-벤즈이미다졸 -4-일] -우레아
Figure imgf000019_0001
Mino) -1H-benzimidazol-4-yl] -urea
Figure imgf000019_0001
4-메틸-피페라진 -1-카르복실산 [6-(8- 쩨틸-퀴나졸린 -2-일아미노) -1Hᅳ벤즈이 4-Methyl-piperazine-l-carboxylic acid [6- (8-meptyl-quinazolin-2-ylamino) -1 H ᅳ benzi
미다졸—4ᅳ일] _아미드 Midazole— 4 single] _amide
H H 피페리딘 -1-카르복실산 [6-(8-메틸—퀴 HH piperidine-1-carboxylic acid [6- (8-methyl-quine
나졸린 -2-일아미노) -1H-벤즈이미다졸- 4-일] -아미드 시 ^人 Nazolin-2-ylamino) -1H-benzimidazol-4-yl] -amide c ^ 人
[2-메틸 -7-(3-피페리딘 -1-일-프로폭시 [2-Methyl-7- (3-piperidin-1-yl-propoxy
메틸 )-3H—벤즈이미다졸 -5-일 H 8-메틸 Methyl) -3H—benzimidazol-5-yl H 8-methyl
-퀴나졸린 -2-일) -아민 T/KR2011/007194 -Quinazolin-2-yl) -amine T / KR2011 / 007194
Figure imgf000020_0001
l-(3-다이메틸아미노-프로필 )-3-[6- (8-이소프로폭시 -퀴나졸린 -2-일아미
Figure imgf000020_0001
l- (3-dimethylamino-propyl) -3- [6- (8-isopropoxy-quinazolin-2-ylami
노) -2-메틸 -1H-벤즈이미다졸 -4-일] -우 레아
Figure imgf000021_0001
No) -2-methyl-1H-benzimidazol-4-yl] -urea
Figure imgf000021_0001
4-메틸-피페라진 -1-카르복실산 [6-(8- 이소프로폭시-퀴나졸린 -2-일아미노) - 2-메틸 -1H-벤즈이미다졸 -4-일] -아미드 4-Methyl-piperazin-1-carboxylic acid [6- (8-isopropoxy-quinazolin-2-ylamino)-2-methyl-1H-benzimidazol-4-yl] -amide
N-[6-(8-이소프로폭시-퀴나졸린 -2-일 N- [6- (8-isopropoxy-quinazolin-2-yl
丫 / 아미노) -2-메틸— 1H-벤즈이미다졸 -4- 일 ]-4-(4-메틸―피페라진 -1-일 )-부틸아 丫 / amino) -2-methyl—1H-benzimidazol- 4 -yl] -4-( 4 -methyl-piperazin-1-yl) -butyla
Η  Η
미드 American drama
[2-사이클로프로필 -6-(8-메틸-퀴나졸 [2-cyclopropyl-6- (8-methyl-quinazole
린 -2-일아미노) - 1H-벤즈이미다졸 -4- 일] -카바민산 에틸 에스터 Lin-2-ylamino) -1H-benzimidazol-4-yl] -carbamic acid ethyl ester
피페라진 -1-일 -[2-(2-트리플루오로메 Piperazin-1-yl-[2- (2-trifluorome
틸 -3H-벤즈이미다졸 -5-일아미노) -퀴나 Tyl-3H-benzimidazol-5-ylamino) -quina
졸린 -7-일] -메탄온Sleepy-7-day] -methanone
Figure imgf000021_0002
Figure imgf000021_0002
2-사이클로프로필 -6ᅳ(8-메틸-퀴나졸린 2-cyclopropyl-6 '(8-methyl-quinazolin
-2-일아미노) -1H—벤즈이미다졸 -4-카르 -2-ylamino) -1H—benzimidazole-4-car
복실산 (2-피페리딘 -1-일-에틸) -아미 1ᅳ [2—사이클로프로필 -6-(8ᅳ메틸-퀴나 Acid (2-piperidin-1-yl-ethyl) -ami 1 ᅳ [2—cyclopropyl-6- (8 ᅳ methyl-quina
졸린— 2-일아미노) -1H-벤즈이 미다졸 -4- 일 ] -3-(3-다이 메틸아미노-프로필 ) -우 레아 H H H 1 Sleepy— 2-ylamino) -1H-benzimidazol-4-yl] -3- (3-dimethylamino-propyl) -urea H H H 1
4_메틸 _피페라진 카르복실산 [2-사 이클로프로필 -6-(8-메틸-퀴나졸린 -2- 일아미노 )-1Η-벤즈이미다졸 -4-일 ] -아 N人 N 세人 N게! 미드 H H N. 4 _Methyl _piperazin carboxylic acid [ 2 -cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1Η-benzimidazol-4-yl] -a N 人 N N crab! Mead HH N.
4-이소프로필-피페라진— 1-카르복실산 4-isopropyl-piperazine— 1-carboxylic acid
[2-메틸 -6-(8-메틸 -퀴나졸린— 2-일아미¬[2-Methyl-6- (8-methyl-quinazoline— 2-ylami¬
쇼노 N人 N세 노) -1H-벤즈이미다졸 -4-일 ] -아미드  Shono N Person N Seno) -1H-benzimidazol-4-yl] -amide
2- ( 2-사이클로프로필 -3H-벤즈이미다졸 2- (2-cyclopropyl-3H-benzimidazole
-5-일아미노) -퀴나졸린 -7—카르복실산 -5-ylamino) -quinazolin-7-carboxylic acid
메틸 에스터 H Methyl ester H
(4-메틸-피페라진— 1-일 )-[2-(2-트리플 (4-Methyl-piperazin— 1-yl)-[2- (2-triple
루오로메틸 -3H-벤즈이미다졸 -5-일아미 Luoromethyl-3H-benzimidazole-5-ylami
노) -퀴나졸린 -7-일 ] -메탄은 H 모플린 -4-카르복실산 [2-사이클로프로 I Y" No) -quinazolin-7-yl] -methane is H morpholin-4-carboxylic acid [2-cyclopro I Y "
필 -6- ( 8-메틸-퀴나졸린 -2-일아미노) - ^ ^니ᄂ N人 N세 1H-벤즈이 미다졸 -4-일 ] -아미드 94 Phil-6- (8-methyl-quinazolin-2-ylamino)-^ ^ nib N Person N 1H-benzimidazol-4-yl] -amide 94
Figure imgf000023_0001
모폴린 -4-카르복실산 [6- (8-이소프로
Figure imgf000023_0001
Morpholine-4-carboxylic acid [6- (8-isopro
폭시-퀴나졸린 -2-일아미 노) -2-메틸- 1H-벤즈이미 다졸 -4-일 ] -아미드 ᄂ N人 N세 Foxy-quinazolin-2-ylamino) -2-methyl-1H-benzimidazol-4-yl] -amide b N-N
(8-이소프로폭시 -퀴나졸린 -2-일 )-(2- 모폴린 -4-일— 3H-벤즈이미다졸 -5-일 ) - 아민
Figure imgf000024_0001
(8-isopropoxy-quinazolin-2-yl)-(2-morpholin-4-yl— 3H-benzimidazol-5-yl) -amine
Figure imgf000024_0001
4-이소프로필-피페라진 -1-카르복실산 4-isopropyl-piperazine-1-carboxylic acid
[ 6- ( 8-이소프로폭시-퀴나졸린 -2-일아 [6- (8-isopropoxy-quinazolin-2-yl
미 노) -2-메틸 -1H-벤즈이 미다졸 -4-일 ] - 아미드 Η Η γ Mino) -2-methyl-1H-benzimidazol-4-yl] -amide Η Η γ
2- (2-사이클로프로필 -3H-벤즈이미다졸 2- (2-cyclopropyl-3H-benzimidazole
-5-일아미노) -퀴나졸린 -7-카르복실산 -5-ylamino) -quinazolin-7-carboxylic acid
(2-피 페 리딘 -1-일-에틸 ) -아미드 (2-piperidin-1-yl-ethyl) -amide
Η  Η
N6-(8-클로로-퀴나졸린 -2-일 ) -2-메틸- 1H-벤즈이미다졸 -4, 6-다이 아민 N 6- (8-chloro-quinazolin-2-yl) -2-methyl-1H-benzimidazole-4, 6-diamine
4-메틸-피페라진 -1-카르복실산 [6-(8- 클로로-퀴나졸린 -2-일아미노) -2-메틸- 1H-벤즈이미다졸 -4-일 ] -아미드 Η Η N. 4-Methyl-piperazine-1-carboxylic acid [6- (8-chloro-quinazolin-2-ylamino) -2-methyl-1H-benzimidazol-4-yl] -amide Η Η N.
Figure imgf000025_0001
Figure imgf000025_0001
Figure imgf000026_0001
R2011/007194
Figure imgf000026_0001
R2011 / 007194
Figure imgf000027_0001
4-메틸-테트라하이드로-피란 -4-카르복
Figure imgf000027_0001
4-Methyl-tetrahydro-pyran-4-carboxy
실산 [2-메틸 -6-(8-메틸-퀴나졸린 -2- 0 일아미노) -1H-벤즈이미다졸 -4-일] -아
Figure imgf000028_0001
Carboxylic acid [2-methyl-6- (8-methyl-quinazolin-2-0 ylamino) -1H-benzimidazol-4-yl] -a
Figure imgf000028_0001
미드 American drama
2 ,6-다이메틸-모폴린 -4-카르복실산 2,6-dimethyl-morpholine-4-carboxylic acid
[2-메틸 -6-(8-메틸-퀴나졸린 -2-일아미 [2-Methyl-6- (8-methyl-quinazolin-2-ylamimi
노) -1H—벤즈이미다졸 -4-일]—아미드No) -1H—benzimidazol-4-yl] —amide
Figure imgf000028_0002
모폴린 -4-일 -[2-(2-모폴린 -4-일 -3H-벤
Figure imgf000028_0002
Morpholin-4-yl- [2- (2-morpholin-4-yl-3H-bene
즈이미다졸 -5-일아미노) -퀴나졸린 -7- 일] -메탄온 Zimidazole-5-ylamino) -quinazolin-7-yl] -methanone
H  H
[2-사이클로프로필 -6-(8-메틸-퀴나졸 [2-cyclopropyl-6- (8-methyl-quinazole
린 -2-일아미노) -1H-벤즈이미다졸 -4- 일] -모폴린 -4-일-메탄온 Lin-2-ylamino) -1H-benzimidazol-4-yl] -morpholin-4-yl-methanone
0 테트라하이드로—피란 -4-카르복실산  0 tetrahydro-pyran-4-carboxylic acid
[2-사이클로프로필 -6-(8-메틸-퀴나졸 [2-cyclopropyl-6- (8-methyl-quinazole
린 -2-일아미노) -1H-벤즈이미다졸 -4- 人 ^ Q 일] -아미드 Lin-2-ylamino) -1H-benzimidazole-4- 人 ^ Qyl] -amide
N-[2-사이클로프로필 -6-(8-메틸 -퀴나 N- [2-cyclopropyl-6- (8-methyl-quina
졸린 -2-일아미노) -1H—벤즈이미다졸 -4- 일] -2-모폴린 -4-일-아세트아미드Sleepy-2-ylamino) -1H-benzimidazol-4-yl] -2-morpholin-4-yl-acetamide
Figure imgf000028_0003
Figure imgf000028_0003
Figure imgf000029_0001
Nj게
Figure imgf000029_0001
Nj crab
N-[2-사이클로프로필— 6- (8-메틸-퀴나 N- [2-cyclopropyl— 6- (8-methyl-quina
85 졸린 -2-일아미노) -1H-벤즈이미다졸 -4- 일] -4-모폴린 -4—일 -벤즈아미드  85 zolin-2-ylamino) -1H-benzimidazol-4-yl] -4-morpholine-4—yl-benzamide
3-플루오로 -N-[2-메틸 -6-(8-메틸-퀴나 3-fluoro-N- [2-methyl-6- (8-methyl-quina
86 졸린 -2-일아미노) -1H-벤즈이미다졸 -4- 일] -5-모폴린 -4-일-벤즈아미드  86 zolin-2-ylamino) -1H-benzimidazol-4-yl] -5-morpholine-4-yl-benzamide
N- [2-사이클로프로필 -6-(8-메틸-퀴나 N- [2-cyclopropyl-6- (8-methyl-quina
졸린 -2-일아미노) -1H-벤즈이미다졸 -4- Sleepy-2-ylamino) -1H-benzimidazole-4-
87 87
일 ]-3-플루오로 -5-모폴린 -4-일-벤즈아  Yl] -3-fluoro-5-morpholin-4-yl-benzia
미드 모폴린 -4-설폰산 [2사이클로프로필- Mid morpholine 4-sulfonic acid [2-cyclopropyl-
88 6-(8-메틸-퀴나졸린 -2-일아미노) -1H- 벤즈이미다졸 -4—일]—아미드88 6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazole-4—yl] —amide
Figure imgf000030_0001
Figure imgf000030_0001
1- [2-사이클로프로필— 6-(8-메틸-퀴나 1- [2-cyclopropyl— 6- (8-methyl-quina
89 졸린 -2-일아미노) -1H-벤즈이미다졸 -4- 일] -3-(3-모폴린 -4-일-페닐) -우레아 Λ Ν人 Λ세 89 Zolin-2-ylamino) -1H-benzimidazol-4-yl] -3- (3-morpholin-4-yl-phenyl) -urea Λ Ν人 Λ three
N-[2-메틸 -6-(8-메틸-퀴나졸린—2-일아 N- [2-methyl-6- (8-methyl-quinazolin-2-yl
90 미노) -1H-벤즈이미다졸 -4-일]—니코틴  90 mino) -1H-benzimidazol-4-yl] —nicotine
아미드
Figure imgf000030_0002
Figure imgf000031_0001
Figure imgf000032_0001
amides
Figure imgf000030_0002
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
2-사이클로프로필 -6-(8—메틸ᅳ퀴나졸린
Figure imgf000033_0001
2-cyclopropyl-6- (8—methylkequinazolin
ᅳ2-일아미노) -1H-벤즈이미다졸— 4-카르  ᅳ 2-ylamino) -1H-benzimidazole— 4-car
109  109
복실산 [3-(4-메틸-피페라진 -1-일 ) -페  Acid [3- (4-Methyl-piperazin-1-yl) -pe
닐 ] -아미드  Neil] -amide
6-(8-메틸-퀴나졸린—2-일아미노 )-1Η-6- (8-methyl-quinazolin-2-ylamino) -1Η-
110 벤조트리아졸 -4-카르복실산 (4—모폴린 110 Benzotriazole-4-carboxylic acid (4—morpholine
-4-일—페닐 ) -아미드 0 "-^ -4-yl-phenyl) -amide 0 "-^
1- [2-이소프로필 -6-(8-메틸-퀴나졸린-1- [2-isopropyl-6- (8-methyl-quinazolin-
111 2-일아미노) -1H-벤즈이 미다졸— 4-일 ] - Y 쎄 "111 2-ylamino) -1H-benzimidazol— 4-yl]-Y Se "
3- (4-모폴린 -4-일-페닐 )-우레아 HΛ HΝ人 3- (4-morpholin-4-yl-phenyl) -urea HΛ H Ν人
H Λ  H Λ
2-메틸 -6-(8-메틸-퀴나졸린 -2-일아미 2-methyl-6- (8-methyl-quinazolin-2-ylami
112 노)— 1H-벤즈이 미 다졸 -4-카르복실산  112 furnace) — 1H-benzimidazole-4-carboxylic acid
(4-모폴린 -4-일-페닐 ) -아미드 (4-morpholin-4-yl-phenyl) -amide
Figure imgf000034_0001
Figure imgf000034_0001
N-[2-사이클로프로필— 6-(8-메틸-퀴나  N- [2-cyclopropyl— 6- (8-methyl-quina
졸린 -2-일아미 노) -1H-벤즈이 미다졸 -4- Sleepy-2-ylamino) -1H-benzimidazole-4-
113 113
일 ] -3-(4-메틸—피페라진 -1-일 ) -벤즈아  General] -3- (4-methyl-piperazin-1-yl) -benza
미드  American drama
1-[2-사이클로프로필 -1-메틸 -6-(8-메  1- [2-cyclopropyl-1-methyl-6- (8-meth
틸-퀴나졸린 -2-일아미노)— 1H-벤즈이 미  Thi-quinazolin-2-ylamino) — 1H-benzimi
114  114
다졸 -4-일 ]— 3-(4-모폴린 -4-일-페닐 ) - Dazol-4-yl] — 3- (4-morpholin-4-yl-phenyl)-
H H H H H H
우레아
Figure imgf000035_0001
2-이소프로필 -6-(8—메틸-퀴나졸린 -2- 일아미노) -1H-벤즈이미다졸 -4-카르복 Urea
Figure imgf000035_0001
2-isopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazole-4-carboxy
121  121
실산 (3-모폴린—4-일메틸-페닐) -아미  Carboxylic acid (3-morpholine—4-ylmethyl-phenyl) -ami
2-메틸 -6-(8-메틸-퀴나졸린 -2-일아미 2-methyl-6- (8-methyl-quinazolin-2-ylami
122 노) -1Η-벤즈이미다졸 -4-카르복실산 122 no) -1Η-benzimidazole-4-carboxylic acid
Figure imgf000036_0001
Figure imgf000036_0001
(3-모폴린 -4-일메틸-페닐 ) -아미드  (3-morpholine-4-ylmethyl-phenyl) -amide
모폴린—4-카르복실 산 [1,2-다이메틸- Morpholine—4-carboxylic acid [1,2-dimethyl-
123 6-(8-메틸-퀴나졸린 -2-일아미노) -1Η- ίΎ 123 6- (8-methyl-quinazolin-2-ylamino) -1Η- ίΎ
벤즈이미다졸 -4-일] -아미드 ^시 ᄂ N人 N세  Benzimidazol-4-yl] -amide ^ c
[2-사이클로프로필 -1-메틸一 6-(8-메틸-[2-Cyclopropyl-1-methyl one 6- (8-methyl-
124 퀴나졸린 -2-일아미노) -1Η-벤즈이미다 124 quinazolin-2-ylamino) -1Η-benzimida
졸 -4-일] -메틸-카바민산 에틸 에스터
Figure imgf000036_0002
Zol-4-yl] -methyl-carbamic acid ethyl ester
Figure imgf000036_0002
[1,4' ]바이피페리딘일 -Γ-일 -[2-메틸-[1,4 '] bipiperidinyl -Γ-yl-[2-methyl-
125 6-(8-메틸-퀴나졸린 -2-일아미노) -1Η- 벤즈이미다졸 -4-일] -메탄온 0 125 6- (8-Methyl-quinazolin-2-ylamino) -1Η-benzimidazol-4-yl] -methanone 0
모폴린 -4-카르복실산 [6-(8-메틸 -퀴나 Morpholine-4-carboxylic acid [6- (8-methyl-quina
126 졸린 -2-일아미노) -1H—벤조트리아졸 -4- 일] -아미드
Figure imgf000036_0003
N-[l,2-다이메틸 -6-(8-메틸-퀴나졸린-126 zolin-2-ylamino) -1H—benzotriazol-4-yl] -amide
Figure imgf000036_0003
N- [l, 2-dimethyl-6- (8-methyl-quinazolin-
127 2-일아미노) - 1H-벤즈이미다졸 -4-일] - 4-모폴린 -4—일메틸-벤즈아미드127 2-ylamino) -1H-benzimidazol-4-yl]-4-morpholine-4—ylmethyl-benzamide
Figure imgf000037_0001
Figure imgf000037_0001
4-메틸-피페라진 -1-카르복실산 [1,2- (γ 4-Methyl-piperazine-1-carboxylic acid [1,2- (γ
128 다이메틸 -6- (8-메틸-퀴나졸린 -2-일아  128 dimethyl-6- (8-methyl-quinazolin-2-yl)
人 Ν Ν Η Η人 1 1 미노) -1H-벤즈이미다졸 -4-일] -아미드  人 Ν Ν Η Η 人 1 1 Mino) -1H-benzimidazol-4-yl] -amide
모폴린 -4—카르복실산 [ 1-에틸 -2-메틸-Morpholine-4—carboxylic acid [1-ethyl-2-methyl-
129 6-(8-메틸—퀴나졸린 -2-일아미노) -1H- 벤즈이미다졸 -4-일] -아미드129 6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -amide
Figure imgf000037_0002
모폴린 -4—카르복실산 [2-사이클로프로
Figure imgf000037_0002
Morpholine-4—carboxylic acid [2-cycloprop
130 필 -6-(8-메틸―퀴나졸린 -2-일아미노) - 니 ^N 130 Phil-6- (8-methyl-quinazolin-2-ylamino) -ni ^ N
1H-벤즈이미다졸 -4-일] -메틸 -아미드 모폴린 -4-카르복실산 [2-사이클로프로  1H-benzimidazol-4-yl] -methyl-amide morpholine-4-carboxylic acid [2-cyclopro
필 -1-메틸 -6— (8-메틸―퀴나졸린 -2-일아  Phil-1-methyl-6— (8-methyl-quinazolin-2-yl
131  131
미노) -1H-벤즈이미다졸 -4-일] -메틸-아  Mino) -1H-benzimidazol-4-yl] -methyl-a
Ν ^^ Ν人 Ν 미드  Ν ^^ Ν 人 Ν mid
4-이소프로필-피페라진 -1-카르복실산  4-isopropyl-piperazine-1-carboxylic acid
[1,2-다이메틸 -6-(8-메틸-퀴나졸린 -2- (Υ  [1,2-dimethyl-6- (8-methyl-quinazolin-2- (iii)
132  132
일아미노) -1H-벤즈이미다졸 -4-일 ] -아 시^ Ν Ν  Monoamino) -1H-benzimidazol-4-yl] -aci ^ Ν Ν
Η Η人 I 1 미드 丫 07194 Η Η 人 I 1 Mid 丫 07194
Figure imgf000038_0001
테트라하이드로-피 란 -4ᅳ카르복실산 [2-사이클로프로필 -1-에틸 -6-(8—메틸-
Figure imgf000038_0001
Tetrahydro-pyran-4 ᅳ carboxylic acid [2-cyclopropyl-1-ethyl-6- (8—methyl-
139 139
퀴나졸린 -2-일아미노) -1H—벤즈이미다 졸 -4-일 ] -아미드  Quinazolin-2-ylamino) -1H—benzimidazol-4-yl] -amide
N-U-에 틸 -2-메틸 -6-(8-메틸-퀴나졸린 I -2-일아미노) -1H-벤즈이미다졸 -4-일 ] - 2-모폴린 -4-일ᅳ아세트아미드 테트라하이드로-피 란 -4-카르복실산 [ 1-에틸 -2-메틸 -6-(8-메틸-퀴나졸린-NU-ethyl-2-methyl-6- (8-methyl-quinazolin I-2-ylamino) -1H-benzimidazol-4-yl] -2-morpholine-4-yl acetamide tetrahydro -Pyran-4-carboxylic acid [1-ethyl-2-methyl-6- (8-methyl-quinazolin-
141 141
2-일아미노) -1H-벤즈이미다졸 -4-일 ] - 아미드  2-ylamino) -1H-benzimidazol-4-yl] -amide
N-[2-사이클로프로필 L-에틸 -6-(8-메 틸ᅳ퀴나졸린 -2-일아미노) -1H—벤즈이 D N- [2-cyclopropyl L-ethyl-6- (8-methylkequinazolin-2-ylamino) -1 H—benz D
142 142
다졸 -4-일 ] -2-모폴린 -4-일-아세트아口' Imidazole-4-yl] -2-morpholin-4-yl-acetamidinium口'
N-[2-사이클로프로필 -1-에 틸 -6-(8-메 틸-퀴나졸린—2-일아미노) -1H-벤즈이口' N- [2-cyclopropyl-1-ethyl-6- (8-methyl-quinazolin—2-ylamino) -1 H-benzig '
143 143
다졸 -4-일 ] -2-다이메틸아미 노-아세트 아미드  Dazol-4-yl] -2-dimethylamino-acetamide
2， 6-다이메틸-모폴린 -4-카르복실산 [2-사이클로프로필 -1-에틸 -6-(8-메틸- 2, 6-dimethyl-morpholine-4-carboxylic acid [2-cyclopropyl-1-ethyl-6- (8-methyl-
144 144
퀴나졸린 -2-일아미노) -1H-벤즈이미다 졸 -4-일 ] -아미드
Figure imgf000040_0001
R2011/007194 Quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -amide
Figure imgf000040_0001
R2011 / 007194
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
본 발명에 따른 화학식 (I)의 화합물은 무기산 또는 유기산으로부터 유도된 약학적으로 허용 가능한 염 형태로 사용될 수 있으며, 이러한 약학적으로 허용가능한 염에는 약제학적으로 허용되는 음이온을 함유하는 무독성 산부가염을 형성하는 산， 예를 들면 염산， 황산， 질산， 인산, 브롬화수소산， 요오드화수소산 등과 같은 무기산， 타타르산， 포름산, 시트르산， 아세트산， 트리'클로로아세트산， 트리플루오로아세트산， 글루콘산， 벤조산， 락트산， 푸마르산, 말레인산 등과 같은 유기 카본산， 메탄설폰산， 벤젠설폰산, P-를투엔설폰산 또는 나프탈렌설폰산 등과 같은 설폰산 등에 의해 형성된 산부가염, 특히 바람직하게는 황산， 메탄설폰산 또는 할로겐화수소산 등에 의해 형성된 산부가염을 들 수 있다.
Figure imgf000045_0001
Figure imgf000046_0001
The compounds of formula (I) according to the invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids, which include non-toxic acid addition salts containing pharmaceutically acceptable anions. forming acid, for example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, inorganic acids, such as hydroiodic acid, tartaric acid, formic acid, citric acid, acetic acid, tri, chloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, Acid addition salts formed by organic carbon acids such as fumaric acid and maleic acid, methanesulfonic acid, benzenesulfonic acid, sulfonic acids such as P-toluenesulfonic acid or naphthalenesulfonic acid, and the like, particularly preferably sulfuric acid, methanesulfonic acid or hydrofluoric acid The acid addition salt formed by this is mentioned.
상기 화학식 (I)의 화합물의 약제학적으로 허용가능한 염은 통상적인 방법들을 사용하여 화학식 (I)의 화합물로부터 제조하여 사용할 수 있다. 구체적으로는 본 발명에 따른 약제학적으로 허용가능한 염은, 화학식 (I)의 화합물을 수혼화성 유기용매， 예를 들면 아세톤， 메탄올， 에탄을， 또는 아세토니트릴 등에 녹이고 과량의 유기산을 가하거나 무기산의 산 수용액을 가한 후 침전시키거나 결정화시켜서 제조할 수 있다. 이어서 이 흔합물에서 용매나 과량의 산을 증발시킨 후 건조시켜서 부가염을 얻거나 또는 석출된 염을 흡인 여과시켜 제조할 수 있다. Pharmaceutically acceptable salts of the compounds of formula (I) are conventional Methods can be prepared and used from compounds of formula (I). Specifically, pharmaceutically acceptable salts according to the present invention may be prepared by dissolving a compound of formula (I) in a water-miscible organic solvent such as acetone, methanol, ethane, or acetonitrile and adding an excess of an organic acid or an inorganic acid. It can be prepared by adding an aqueous acid solution followed by precipitation or crystallization. This mixture can then be evaporated and dried to evaporate the solvent or excess acid to obtain additional salts or to precipitate prepared salts by suction filtration.
본 발명에 따른 화학식 (I)의 화합물은 이로부터 제조될 수 있는 수화물 및 용매화물로 사용될 수 있다.  The compounds of formula (I) according to the invention can be used as hydrates and solvates which can be prepared therefrom.
또한 본 발명에 따른 화학식 (I)의 화합물은 비대칭 탄소중심을 가질 수 있으므로， 이의 약학적으로 허용가능한 염 뿐만 아니라， 이로부터 제조될 수 있는 In addition, the compound of formula (I) according to the present invention may have an asymmetric carbon center, so that not only pharmaceutically acceptable salts thereof, but also can be prepared therefrom
R또는 S 이성질체， 라세믹 화합물， 부분입체, 이성질체 흔합물， 및 개개 부분입체 이성질체로서 포함할 수 있으며， 이들 용매화물， 수화물, 이성질체 및 이들의 혼합물 또한 본 발명의 범위에 포함된다. 상기 화학식 (I)의 화합물， 또는 이의 약제학적으로 허용가능한 염, 이성질체, 수화물 또는 용매화물은 SYK, JA 3, FLT3, FLT2, PDGFR (PDGFRA) , TRKA (NTRKl) , KDR, CD 2/cycA, AurA (AURKA) ERK, PI3K, Raf, PYK2 및 RET 등의 단백질 키나제에 대한 활성을 억제할 수 있으므로， 상기 단백질 키나제에 의해 유도된 비정상적인 세포 반웅과 관련된 질환의 치료를 위해 사용될 수 있다. R or S isomers, racemic compounds, diastereomers, isomeric mixtures, and individual diastereomers, and these solvates, hydrates, isomers and mixtures thereof are also included in the scope of the present invention. The compound of formula (I), or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof, may be SYK, JA 3, FLT3, FLT2, PDGFR (PDGFRA), TRKA (NTRKl), KDR, CD 2 / cycA, AurA (AURKA) can inhibit the activity of protein kinases such as ERK, PI3K, Raf, PYK2 and RET, and thus can be used for the treatment of diseases associated with abnormal cell reactions induced by said protein kinases.
이에 따라 본 발명은 상기 화학식 (I)의 화합물, 및 이의 약제학적으로 허용가능한 염, 이성질체， 수화물 및 용매화물로 이루어진 군에서 선택되는 화합물의 단백질 키나제에 의해 유도된 비정상적인 세포 반응과 관련된 질환의 예방 또는 치료용 용도를 제공한다. 또한, 본 발명은 상기 화학식 (I)의 화합물, 및 이의 약제학적으로 허용가능한 염 이성질체， 수화물 및 용매화물로 이루어진 군에서 선택되는 화합물의 유효량을 이를 필요로 하는 포유동물에게 투여하는 것을 포함하는， 단백질 키나제에 의해 유도된 비정상적인 세포 반웅과 관련된 질환의 예방 또는 치료방법을 제공한다. 또한， 본 발명은 상기 화학식 (I)의 화합물， 및 이의 약제학적으로 허용가능한 염， 이성질체, 수화물 및 용매화물로 이루어진 군에서 선택되는 화합물을 유효성분으로 포함하는， 단백질 키나제의 활성 억제제를 제공한다. Accordingly, the present invention provides a method for the prevention of diseases associated with abnormal cellular responses induced by protein kinases of a compound of formula (I), and a compound selected from the group consisting of pharmaceutically acceptable salts, isomers, hydrates and solvates thereof. Or for therapeutic use. In addition, the present invention is selected from the group consisting of the compound of formula (I), and pharmaceutically acceptable salt isomers, hydrates and solvates thereof Provided are methods for the prevention or treatment of diseases associated with abnormal cell reactions induced by protein kinases, comprising administering an effective amount of a compound to a mammal in need thereof. The present invention also provides an activity inhibitor of protein kinase comprising the compound of formula (I), and a compound selected from the group consisting of pharmaceutically acceptable salts, isomers, hydrates and solvates as an active ingredient. .
또한， 본 발명은 유효성분으로서 상기 화학식 (I)의 화합물， 이의 약제학적으로 허용가능한 염， 이성질체， 수화물 및 용매화물로 이루어진 군에서 선택되는 화합물 및 약학적으로 허용가능한 담체를 포함하는， 단백질 키나제에 의해 유도된 비정상적인 세포 반웅과 관련된 질환의 예방 또는 치료용 약학 조성물을 제공한다. In addition, the present invention is a protein kinase comprising a compound selected from the group consisting of the compound of formula (I), pharmaceutically acceptable salts, isomers, hydrates and solvates and a pharmaceutically acceptable carrier as an active ingredient It provides a pharmaceutical composition for the prevention or treatment of diseases associated with abnormal cell reaction induced by.
상기 질환은 단백질 키나제의 과발현 및 이에 따른 비정상적인 세포 반응에 의해 야기될 수 있는 모든 질환을 포함하며, 구체적으로는 면역질환， 자가면역질환, 염증질환， 골질환, 대사아상, 신경정신질환， 퇴행성 뇌질환， 암， 심장질환， 알레르기질환， 천식， 알츠하이머 및 호르몬 관련 질환을 들 수. 있으나， 이에 한정되는 것은 아니다.  The disease includes all diseases that can be caused by overexpression of protein kinases and thus abnormal cell responses, and specifically, immune diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, neuropsychiatric disorders, and degenerative brain. Diseases, cancer, heart disease, allergic diseases, asthma, Alzheimer's and hormone-related diseases. However, it is not limited thereto.
상기 약학 조성물은 약학적으로 허용 가능한 담체 또는 비히클을 함께 포함할 수 있다..  The pharmaceutical composition may comprise a pharmaceutically acceptable carrier or vehicle together.
본 발명의 약학 조성물은 통상적인 방법에 따라 제제화할 수 있으며, 정제， 환제， 산제， 갑샐제， 시럽， 에멀견， 마이크로에멀견 등의 다양한 경구 투여 형태 또는 근육내， 정맥내 또는 피하투여와 같은 비경구 투여 형태로 제조될 수 있다. 경구투여를 위한 고형제제로 제조되는 경우， 사용가능한 담체의 예로는, 전분， 탄산칼슘， 수크로스 (sucrose), 락토오스 (lactose) , 젤라틴， 마그네슘 스테아레이트， 탈크 등을 사용할 수 있다.  The pharmaceutical compositions of the present invention may be formulated according to conventional methods and may be used in various oral dosage forms, such as tablets, pills, powders, tablets, syrups, emulsions, microemulsions, or intramuscular, intravenous or subcutaneous administration. It may be prepared in a parenteral dosage form. When prepared as a solid preparation for oral administration, examples of the carrier usable include starch, calcium carbonate, sucrose, lactose, gelatin, magnesium stearate, talc and the like.
또한 현탁제， 내용액제, 유제 또는 시럽제 등의 경구 투여를 위한 액상 제제로 제조되는 경우에 사용가능한 담체의 예로는， 단순 회석제인 물, 리퀴드 파라핀 등의 희석제 및 습윤제, 감미제， 방향제 또는 보존제 등을 들 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액， 비수성용제， 현탁용제， 유제, 동결건조제제 또는 좌제가 포함된다. 상기 비수성용제 또는 현탁용제로 제조되는 경우에 사용가능한 담체의 예로는， 프로필렌글리콜, 플리에틸렌 글리콜， 올리브 오일과 같은 식물성 기름， 에틸올레이트와 같은 주사 가능한 에스테르 등을 들 수 있으며， 좌제로 제조되는 경우에 사용가능한 담체로는 위텝솔， 마크로골, 트원 61, 카카오지, 라우린지， 글리세를 또는 젤라틴 등을 들 수 있다. In addition, liquids for oral administration such as suspensions, liquid solutions, emulsions or syrups Examples of the carrier usable in the preparation of the preparation include water which is a simple diluent, diluents such as liquid paraffin and wetting agents, sweeteners, fragrances or preservatives. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations or suppositories. Examples of the carrier usable when prepared with the non-aqueous solvent or the suspension solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like. Carriers usable in this case include witepsol, macrogol, twenty-one, cacao butter, laurin butter, glycerol or gelatin.
또한， 본 발명에 따른 화합물 등의 유효성분의 인체 투여량은 환자의 나이， 몸무게, 성별， 투여 형태， 건강 상태 및 질환 정도에 따라 달라질 수 있으며， 몸무게가 70 kg인 성인 환자를 기준으로 할 때， 일반적으로는 1.0 mg 내지 10,000 mg/일, 바람직하게는 10 mg 내지 3,000 nig/일이며， 일정시간 간격으로 1일 1회 내지 수회에 분할 투여할 수도 있다. 본 발명의 일 실시양태에 따른 상기 화학식 (I)의 화합물 (화학식 (I)에서 In addition, the human dose of the active ingredient, such as the compound according to the present invention may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, when the weight is 70 kg based on an adult patient It is generally 1.0 mg to 10,000 mg / day, preferably 10 mg to 3,000 nig / day, and may be dividedly administered once to several times a day at regular intervals. According to an embodiment of the present invention, the compound of formula (I)
W가 -C-R3이고， X가 N이고， Y가 NH이고， A가 -NH-C0—인 화합물)은 하기 반응식 1에 도시된 바와 같은 제조과정에 의해 제조될 수 있다: W is —C—R 3, X is N, Y is NH, and A is —NH—C 0—, which may be prepared by a manufacturing process as shown in Scheme 1 below:
[반응식 1] Scheme 1
Figure imgf000050_0001
Figure imgf000050_0001
Toluene^THF EtDH  Toluene ^ THF EtDH
Figure imgf000050_0002
Figure imgf000050_0002
상기 식에서，  In the above formula,
Rl, R2, R3 및 B는 상기 화학식 (I)에서 정의된 바와 같다. 구체적으로， 상기 반웅식 1에서 나타난 바와 같이， 2-플루오로 벤조산 (1)을 질산 및 황산 흔합물을 용매로 하여 니트로화 반응을 통해 3，5-다이니트로一 2一 프루오로벤조산 (2)을 얻은 후 암모니아수로 처리하여 3， 5ᅳ다이니트로ᅳ 2- 아미노벤조산 (3)을 얻을 수 있다ᅳ 이를 암모니움설파이드 수용액에서 가열하여 3- 니트로기만을 선택적으로 아미노기로 치환시켜 2， 3-다이아미노ᅳ 5一 니트로벤조산 (4)을 제조할 수 있다. 상기에서 제조된 2，3—다이아미노ᅳ 5一 0 R1, R2, R3 and B are as defined in formula (I) above. Specifically, as shown in the reaction formula 1, through the nitration reaction of 2-fluoro benzoic acid (1) with a nitric acid and sulfuric acid mixture as a solvent, 3,5-dinitrol 2 one fluorobenzoic acid (2 ), And then treated with ammonia water to obtain 3,5'dinitrotropy 2-aminobenzoic acid (3). It is heated in an aqueous solution of ammonium sulfide to selectively substitute only the 3-nitro group with an amino group. Diamino # 5 one nitrobenzoic acid (4) can be manufactured. 2，3—diamino ᅳ 5 一 prepared above 0
니트로벤조산을 에탄올을 용매로 하여 H R3 (5) (예를 들어， 알데하이드， 카르복실산 또는 카르복실산 무수물)와 반응시켜 환류 교반함으로써 벤조 이미다졸 유도체 (6)들을 얻을 수 있다. 상기에서 제조된 벤즈이미다졸 유도체를 옥살릴 클로라이드 조건 하에서 다이메틸설폭시드 (DMF), 및 다이클로로메탄 (DMC) 및 테트라하이드로퓨란 (THF)의 존재 하에 반응시켜 액시드 클로라이드를 얻고， 바로 소듐아자이드를 처리하여 벤즈이미다졸의 아자이드 유도체 (7)들을 얻을 수 있다. 상기에서 제조된 벤즈이미다졸의 아자이드 유도체를 커티어스 반응을 통해 카바메이트 화합물 (8)을 합성하고 팔라듐 촉매를 이용한 수소화 반응 또는 철 /염화 암모늄을 이용한 환원 반웅을 통해 니트로기를 아미노기로 전환하여 화합물 (9)를 제조한다. The benzoimidazole derivatives (6) can be obtained by reacting nitrobenzoic acid with H R3 (5) (for example, aldehyde, carboxylic acid or carboxylic anhydride) using ethanol as a solvent and reflux stirring. The benzimidazole derivative prepared above was reacted in the presence of dimethylsulfoxide (DMF), and dichloromethane (DMC) and tetrahydrofuran (THF) under oxalyl chloride conditions to obtain an acid chloride, Treatment of the id can yield azide derivatives (7) of benzimidazole. Synthesizing the carbamate compound (8) with the azide derivative of benzimidazole prepared above through a Curtis reaction and converting the nitro group to an amino group through a hydrogenation reaction using a palladium catalyst or a reduction reaction using iron / ammonium chloride (9) is manufactured.
이어， 상기에서 얻어진 화합물 (9)를 퀴나졸린 유도체 (예를 들면， 2-클로로 퀴나졸린 화합물 (10))과 중합 반웅을 하여 아미노 퀴나졸린 화합물 (11)을 제조할 수 있다. 제조된 아미노 퀴나졸린 화합물 (11)은 수산화나트륨 수용액을 이용하여 카바메이트를 분해함으로써 벤즈이미다졸의 4-위치에 아미노기가 도입된 화합물 (12)를 제조한다. 제조된 화합물 (12)의 화합물을 할로 카보닐 화합물 (13)과 용매 중에 반웅시킴으로써, 본원 발명의 화학식 (I)의 화합물을 제조할 수 있다. 본 발명의 다른 실시양태에 따른 상기 화학식 (I)의 화합물 (화학식 (I)에서 W가 -C-R3이고， X가 N이고， Y가 NH이고， A가 -NH-C0-인 화합물)은 하기 반웅식 2에 도시된 바와 같은 제조과정에 의해 제조될 수 있다: Subsequently, the compound (9) obtained above is subjected to polymerization reaction with a quinazoline derivative (for example, 2-chloro quinazoline compound (10)) to produce an amino quinazoline compound (11). The prepared amino quinazoline compound (11) decomposes the carbamate using an aqueous sodium hydroxide solution to prepare a compound (12) in which an amino group is introduced at the 4-position of benzimidazole. The compound of formula (I) of the present invention can be prepared by reacting the compound of the prepared compound (12) in a halocarbonyl compound (13) and a solvent. According to another embodiment of the present invention, the compound of formula (I) (in formula (I), W is -C-R3, X is N, Y is NH, and A is -NH-C0-) It can be prepared by the manufacturing process as shown in Banung Formula 2:
[반응식 2] Scheme 2
Figure imgf000052_0001
Figure imgf000052_0001
상기 식에서，  In the above formula,
Rl, R2, R3 및 B는 화학식 (I)에서 정의된 바와 같다. 구체적으로， 상기 반웅식 2에서 나타난 바와 같이， 상기 반웅식 1에 기재된 방식으로 제조된 니트로 벤즈이미다졸의 카바메이트 중간체 (즉 화합물 (9))를 수산화나트륨 수용액으로 처리하여 화합물 (14)를 제조한다. 이어， 상기 화합물 (14)의 4-위치 아미노기에 할로 카보닐기를 도입하여 화합물 (15)를 제조한 후， 상기 화합물의 니트로기를 팔라듐 촉매를 이용한 수소화 반웅 또는 철 /염화 암모늄을 이용한 환원 반웅을 통해 아미노기로 환원시켜 화합물 (16)을 제조할 수 있다. 이어， 상기 화합물 (16)을 퀴나졸린 유도체 (예를 들면， 2-클로로 퀴나졸린 화합물 (10))과 중합 반응시킴으로써, 본원 발명의 화학식 (I)의 화합물을 제조할 수 있다. 본 발명의 또 다른 실시양태에 따른 상기 화학식 (I)의 화합물 (화학식 R1, R2, R3 and B are as defined in formula (I). Specifically, as shown in the reaction formula 2, the carbamate intermediate of nitro benzimidazole (ie compound (9)) prepared in the manner described in the reaction formula 1 was treated with an aqueous sodium hydroxide solution to prepare a compound (14). do. Subsequently, the compound (15) was prepared by introducing a halocarbonyl group into the 4-position amino group of the compound (14), and then the nitro group of the compound was subjected to hydrogenation reaction using a palladium catalyst or reduction reaction using iron / ammonium chloride. Compound (16) can be prepared by reduction with an amino group. Subsequently, the compound of formula (I) of the present invention can be prepared by polymerizing the compound (16) with a quinazoline derivative (for example, 2-chloro quinazoline compound (10)). A compound of formula (I) according to another embodiment of the invention
(I)에서 W가 -C-R3이고, X가 N이고， Y가 NH이고, A가 우레아인 화합물)은, 우레아 링커를 도입하는 경우， 하기 반웅식 3에서 나타난 바와 같이， 화합물 (14)를 RNC0와 반응시킬 수 있다. 이후 과정은 상기 반응식 2에 나타난 바와 동일한 방식으로 수행함으로써, 본원 발명의 화학식 (I)의 화합물을 제조할 수 있다: In (I), W is -C-R3, X is N, Y is NH, and A is urea), when introducing a urea linker, as shown in the following reaction formula 3, compound (14) With RNC0 Can react. The following procedure can be carried out in the same manner as shown in Scheme 2 to prepare a compound of formula (I) of the present invention:
[반웅식 3] [Banungsik 3]
Figure imgf000053_0001
Figure imgf000053_0001
상기 식에서,  Where
R3 및 B는 화학식 (I)에서 정의된 바와 같다.  R3 and B are as defined in formula (I).
<벤즈이미다졸 유도체의 제조 > <Preparation of Benzimidazole Derivatives>
본 발명에 따르면, 1-알킬 벤즈이미다졸 유도체는 하기 반응식 4에서 나타난 바와 같은 제조방법에 따라 제조될 수 있다.  According to the present invention, the 1-alkyl benzimidazole derivative can be prepared according to the preparation method as shown in Scheme 4 below.
[반응식 4] Scheme 4
Figure imgf000053_0002
상기 식에서，
Figure imgf000053_0002
In the above formula,
A, B 및 R3은 화학식 (I)에서 정의된 바와 같다. 구체적으로， 반응식 1에서 제조된 화합물 (8) 또는 최종 화합물 (I)를 1H 벤즈이미다졸을 아세톤에 녹인 후， 막자사발에서 갈아 준비한 K0H 2당량을 넣은 후 상은에서 30분 .교반한다. 이어， 상기 반응 흔합물에 할로알칸 (예를 들어， 요오드화메탄， 클로로메탄， 요오드화에탄， 클로로에탄 또는 브로모에탄)을 1당량을 적가한 후 3시간 동안 환류 교반한다. 제조된 반응 혼합물을 농축시켜 물로 회석한 후 에틸아세테이트 (EA)로 추출하고 무수 Na2S¾로 건조한 후 감압농축한다. 실리카와 에틸아세테이트 /핵산 또는 메탄올 /다이클로로메탄을 이용한 크로마토그래피를 통해 수율로 생성물을 얻었다. A, B and R3 are as defined in formula (I). Specifically, after dissolving 1H benzimidazole in acetone, the compound (8) or the final compound (I) prepared in Scheme 1 was added with K0H 2 equivalents prepared in a mortar and stirred for 30 minutes at phase silver. Subsequently, 1 equivalent of haloalkanes (for example, methane iodide, chloromethane, ethane iodide, chloroethane or bromoethane) is added to the reaction mixture. After dropwise addition, the mixture was stirred under reflux for 3 hours. The reaction mixture was concentrated, distilled with water, extracted with ethyl acetate (EA), dried over anhydrous Na 2 S¾ and concentrated under reduced pressure. The product was obtained by chromatography using silica and ethyl acetate / nucleic acid or methanol / dichloromethane.
<퀴나졸린 유도체의 제조 > <Preparation of quinazoline derivatives>
본 발명에 따르면， 퀴나졸린 유도체는 다음과 같은 제조방법에 따라 제조될 수 있다. 구체적으로, 상기 반응식 1 또는 2에서， 벤즈이미다졸 화합물과 중합 반웅에 사용될 수 있는 퀴나졸린 유도체 (예를 들면, 3-클로로 퀴나졸린)는 하기 반웅식 5 또는 6에 기재된 방식에 따라 제조될 수 있다:  According to the present invention, the quinazoline derivative may be prepared according to the following preparation method. Specifically, in Scheme 1 or 2, the quinazoline derivative (eg, 3-chloro quinazoline) that can be used in the polymerization reaction with the benzimidazole compound can be prepared according to the method described in the following reaction formula 5 or 6 have:
[반응식 5]
Figure imgf000054_0001
Scheme 5
Figure imgf000054_0001
상기 식에서，  In the above formula,
R1 및 R2는 상기 화학식 (I)에서 정의된 바와 같다. 상기 반웅식 5에서 나타난 바와 같이， 2-아미노벤조산을 N- 메틸피를리돈 (NMP) 또는 페놀을 용매로 하여 우레아와 함깨 가열하여 1,3- 다이하이드록시 퀴나졸린을 합성한 후， P0C13을 용매로 사용하여 환류 및 교반함으로써 1,3-다이클로로 퀴나졸린을 합성할 수 있다. 상기 제조된 1,3- 다이클로로 퀴나졸린은 팔라듐 촉매의 존재 하에 수소화 반응이나 Zn 및 N¾ 조건에서 선택적으로 염소기를 제거하여 3-클로로 퀴나졸린을 합성할 수 있다. R1 and R2 are as defined in formula (I) above. As shown in the reaction formula 5, 2-aminobenzoic acid is heated with urea using N-methylpyrrolidone (NMP) or phenol as a solvent to synthesize 1,3-dihydroxy quinazoline, and then P0C1 3 1,3-dichloro quinazoline can be synthesized by refluxing and stirring using as a solvent. The prepared 1,3-dichloro quinazoline can be synthesized by hydrogenation in the presence of a palladium catalyst or by selectively removing chlorine groups under Zn and N¾ conditions.
3-클로로 퀴나졸린의 다른 합성 방법으로 하기 반응식 6에 따른 방식을 이용할 수 있다: [반응식 6]
Figure imgf000055_0001
As another method for synthesizing 3-chloroquinazolin, a scheme according to Scheme 6 can be used: Scheme 6
Figure imgf000055_0001
상기 식에서，  In the above formula,
R1 및 R2는 상기 화학식 (I)에서 정의된 바와 같다. 상기 반웅식 6에서 나타난 바와 같이， 2-아미노벤즈알데하이드를 NMP를 용매로 하여 우레아와 함께 가열하여 3-하이드록시 쥐나졸린을 합성한다. 이어， P0C13을 용매로 사용하여 환류 및 교반하여 3-클로로 퀴나졸린을 합성할 수 있다. 한편, 2ᅳ클로로 퀴나졸린 유도체는 하기 반웅식 7에 기재된 방식에 따라 제조될 수 있다: R1 and R2 are as defined in formula (I) above. As shown in the reaction formula 6, 2-aminobenzaldehyde is heated together with urea using NMP as a solvent to synthesize 3-hydroxy musazolin. Then, 3 -chloro quinazoline can be synthesized by refluxing and stirring using P0C1 3 as a solvent. On the other hand, 2 ᅳ chloroquinazoline derivatives can be prepared according to the scheme described in the following formula:
[반웅식 7]
Figure imgf000055_0002
[Bungungsik 7]
Figure imgf000055_0002
상기 반응식 7에서 나타난 바와 같이， 2-아미노벤조산 (1)을 우레아 및 페놀의 존재 하에 반응시켜 다이퀴나졸론 (2)을 제조하고， 이를 P0C!3을 용매로 하여 환류 및 교반함으로써 2,4—다이클로로 퀴나졸린 (3)을 제조할 수 있다. 제조된 2,4- 다이클로로 퀴나졸린 (3)은 Zn 및 NH3 조건에서 선택적으로 염소기를 제거하여 2- 클로로 퀴나졸린을 합성할 수 있다. As shown in Scheme 7, the 2-aminobenzoic acid (1) was reacted in the presence of urea and phenol to prepare diquinazolone (2), which was obtained from P0C! 2,4-dichloro quinazoline (3) can be manufactured by refluxing and stirring 3 as a solvent. The prepared 2,4-dichloro quinazoline (3) can selectively remove chlorine groups under Zn and NH 3 conditions to synthesize 2-chloro quinazoline.
상기 제조된 2-클로로 퀴나졸린 유도체는 상기 기술된 합성방법에 따라 하기 기재된 치환기를 갖는 화합물로 전환될 수 있다: The 2-chloro quinazoline derivatives prepared above can be converted into compounds having the substituents described below according to the synthesis methods described above:
Figure imgf000056_0001
Figure imgf000056_0001
Figure imgf000056_0002
Figure imgf000056_0002
이하， 본 발명을 하기 실시예에 의하여 보다 상세하게 설명하고자 한다. 단 하기 실시예는 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위가 이들만으로 한정되는 것은 아니다. 실시예 I： 2-다이메틸아미노 -N-[2-메틸 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H- 벤즈이미다졸 -4-일] -아세트아미드의 제조 실시예 1-1: 2-클로로퀴나졸린유도체 Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention and the scope of the present invention is not limited thereto. Example I: Preparation of 2-dimethylamino-N- [2-methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -acetamide 1-1: 2-chloroquinazoline derivative
Figure imgf000056_0003
Figure imgf000056_0003
단계 1 Step 1
2-아미노벤조산 (1) (222 g, 1.46 mol), 우레아 (529 g, 8.81 mol) 및 페놀 2-aminobenzoic acid (1) (222 g, 1.46 mol), urea (529 g, 8.81 mol) and phenol
(1200 mL)을 흔합한 후 세시간 동안 환류 교반하였다. 은도를 100°C로 넁각한 후 에탄을 (1200 ml)을 서서히 첨가하였다. 고체 생성물을 여과하고 차가운 에탄올과 물로 씻어 다이퀴나졸론 (2)(220 g)을 85.6 % 수율로 얻었다. (1200 mL) was combined and stirred at reflux for three hours. After immersing the silver at 100 ° C Ethane (1200 ml) was added slowly. The solid product was filtered and washed with cold ethanol and water to give diquinazolone (2) (220 g) in 85.6% yield.
匪 R (400 MHz, DMS0)： δ 11.32 (1H, b, N-H), 10.39 (1H, b, N-H), 7.76 (1H, d, J=7.6 Hz, Ar-H), 7.48 (1H, d, J-7.2 Hz, Ar-H), 7.09 (1H, t, Ar-H), 2.34 (3H, s, Me). 단계 2  匪 R (400 MHz, DMS0): δ 11.32 (1H, b, NH), 10.39 (1H, b, NH), 7.76 (1H, d, J = 7.6 Hz, Ar-H), 7.48 (1H, d, J-7.2 Hz, Ar-H), 7.09 (1H, t, Ar-H), 2.34 (3H, s, Me). Step 2
상기 단계 1에서 제조된 다이퀴나졸론 (2)(114 g, 0.647誦 ol)을 P0C13 (300 mL) 및 Ν,Ν-다이메틸아닐린 (45.6 mL, 0.356 mol)의 혼합액에 고루 섞은 후 5시간 동안 환류 교반하였다. 반웅 혼합물을 얼음에 부어 형성된 고체 생성물을 여과하여 얻은 후 물로 세척하고 진공 하에서 건조하여 2，4-다이클로로 퀴나졸린 (3)(124 g)을 90%수율로 얻었다. Diquinazolone (2) (114 g, 0.647 誦 ol) prepared in step 1 was mixed evenly in a mixture of P0C1 3 (300 mL) and Ν, Ν-dimethylaniline (45.6 mL, 0.356 mol) for 5 hours. Stirred at reflux. The reaction mixture was poured into ice, and the resulting solid product was obtained by filtration, washed with water and dried under vacuum to give 2,4-dichloroquinazolin (3) (124 g) in 90% yield.
'HNMR (400 MHz, DMS0): 58.12 (1H, d, 7=9.2 Hz, Ar-H), 8.02 (1H, d, J=6.8 Hz, Ar-H), 7.78 (1H, t, Ar-H) , 2.65 (3H, s, Me). 단계 3  'HNMR (400 MHz, DMS0): 58.12 (1H, d, 7 = 9.2 Hz, Ar-H), 8.02 (1H, d, J = 6.8 Hz, Ar-H), 7.78 (1H, t, Ar-H ), 2.65 (3H, s, Me). Step 3
상기 단계 2에서 제조된 2,4-다이클로로 퀴나졸린 (75 g, 0.35 mol)의 다이클로로메탄과 9%의 수산화암모니아가 포함된 1.5 L의 NaCl 포화용액 혼합물에 고체가루 상태의 Zn (75 g, 1.15 mol)를 첨가하였다. 상기에서 제조된 반웅 흔합물을 2시간 동안 환류 및 교반하고， 넁각 후 샐라이 ^를 이용해 여과하였다. 여과액의 유기충을 분리하고 물충을 다이클로로메탄으로 추출하였다. 농축하여 남은 물질을 에틸 아세테이트 (1.5L)로 희석하고， 1 노르말 염산용액 (0.2 L)과 물 (0.2 L)로 씻은 후 건조 농축하여 2—클로로 퀴나졸린을 얻었다. 제조된 2-클로로 퀴나졸린을 실리카에서 PE/EA= 100： 1~40：1 (v/v)의 조건에서 크로마토 그래피를 이용하여 54%수율로 순수한 노란색 고체의 2ᅳ클로로 퀴나졸린을 얻었다.  To a 1.5 L NaCl saturated solution mixture containing 2,4-dichloroquinazolin (75 g, 0.35 mol) and 9% ammonia hydroxide prepared in step 2, Zn (75 g) as a solid powder , 1.15 mol) was added. The reaction mixture prepared above was refluxed and stirred for 2 hours, and after being filtered, it was filtered using Salay ^. The organic larvae of the filtrate were separated and the larvae were extracted with dichloromethane. The remaining material was concentrated with ethyl acetate (1.5 L), washed with 1 normal hydrochloric acid solution (0.2 L) and water (0.2 L), and then concentrated to dryness to obtain 2-chloroquinazolin. The prepared 2-chloro quinazoline was chromatographed on silica under conditions of PE / EA = 100: 1 to 40: 1 (v / v) to give 2 ᅳ chloro quinazoline as a pure yellow solid in 54% yield.
]HNMR (400 MHz, CDC13): 9.24 (1H, s, Ar-H) , 7.78 (1H, d, J=7.6 Hz, Ar- ] HNMR (400 MHz, CDC13) : 9.24 (1H, s, Ar-H), 7.78 (1H, d, J = 7.6 Hz, Ar-
H), 7.56 (1H, t, Ar-H) , 2.74 (3H, s, Me). ESI MS: 179 ([M+l] +). 실시예 1-2： 벤즈이미다졸유도체 -(1) H), 7.56 (1H, t, Ar-H), 2.74 (3H, s, Me). ESI MS: 179 ([M + 1] +). Example 1-2: Benzimidazole Derivative-(1)
A: 2, 3-다이아미노 -5-니트로벤조산의 제조 상기 퀴나졸린 유도체와의 중합 반웅에 사용되는 벤즈이미다졸 유도체를 제조하기 위한 중간체인 2， 3-다이아미노— 5—니트로벤조산을 다음과 같이 제조하였다:
Figure imgf000058_0001
A: Preparation of 2, 3-diamino-5-nitrobenzoic acid The intermediate 2, 3-diamino-5-nitrobenzoic acid for preparing the benzimidazole derivative used for the polymerization reaction with the quinazoline derivative is as follows. Prepared as follows:
Figure imgf000058_0001
1 2 3 4  1 2 3 4
단계 1 Step 1
얼음으로 반웅 용기를 냉각시킨 발연황산 (20% S03, 9.0 L)에 발연질산 (4.25 L)을 천천히 적가하였다. 이때 내부 온도가 40°C를 넘지 않도톡 하였다. 발연질산을 적가한 후 냉각 용기를 제거하고 2—플루오로 벤조산 (1.77 kg, 12.6 mol)을 첨가하였다. 상기에서 제조된 반웅 혼합물을 2시간 동안 12CTC로 가열한 후 상온으로 넁각시키고， 넁각된 반응 흔합물을 층분한 양의 얼음에 부었다. 이때 형성된 고체 생성물을 여과하여 얻은 후， 물로 세척하고 진공 건조시켜 흰색 고체의 3， 5ᅳ다이니트로 -2-플루오로벤조산 (2)을 (1.9 kg) 65% 수율로 얻었다. Fuming nitric acid (4.25 L) was slowly added dropwise to fuming sulfuric acid (20% SO 3 , 9.0 L) in which the reaction vessel was cooled with ice. At this time, the internal temperature was not allowed to exceed 40 ° C. After adding nitric acid dropwise, the cooling vessel was removed and 2—fluoro benzoic acid (1.77 kg, 12.6 mol) was added. The reaction mixture prepared above was heated to 12 CTC for 2 hours, and then cooled to room temperature, and the reacted reaction mixture was poured into an amount of ice. The solid product formed at this time was obtained by filtration, washed with water and dried in vacuo to give 3,5'dinitro-2-fluorobenzoic acid (2) as a white solid (1.9 kg) in 65% yield.
¾NMR (400 MHz, DMS0_d6) δ： 9.02 (m, 1H), 8.83 Cm, 1H). MS (ESI-) m/z: 229 [M-l]- 단계 2  ¾NMR (400 MHz, DMS0_d6) δ: 9.02 (m, 1H), 8.83 Cm, 1H). MS (ESI-) m / z: 229 [M−l] − Step 2
상기 단계 1에서 제조된 3， 5-다이니트로 -2-플루오로벤조산 (1.9 kg, 8.26 mol)을 수산화 암모늄 용액 (25%， 20 L)과 섞은 후에 상온에서 1시간 동안 교반하였다. 형성된 고체 생성물을 여과한 후 물에 풀어 섞었다. 상기 흔합물을 4 노르말 농도의 염산 수용액을 첨가하여 pH 4로 산성화 시켰다. 고체를 여과하여 얻은 후 물로 씻어 수율 96%로 2-아미노 -3, 5-다이니트로 벤조산 (3)(1.8 kg)을 노란색 고체상태로 얻었다. 3, 5-dinitro-2-fluorobenzoic acid (1.9 kg, 8.26 mol) prepared in step 1 was mixed with ammonium hydroxide solution (25%, 20 L) and then at room temperature for 1 hour. Stirred. The solid product formed was filtered off and mixed with water. The mixture was acidified to pH 4 by addition of 4 normal aqueous hydrochloric acid solution. The solid was filtered off and washed with water to give 2-amino-3, 5-dinitrobenzoic acid (3) (1.8 kg) as a yellow solid in 96% yield.
蘭 R (400 MHz, DMS0-d6) δ： 8.98 (d, J = 3.2 Hz, 1H), 8.84 (d, J = 3.2 蘭 R (400 MHz, DMS0-d6) δ: 8.98 (d, J = 3.2 Hz, 1H), 8.84 (d, J = 3.2
Hz, 1H). MS (ESI-), m/z: 226 [M-l]- 단계 3 Hz, 1H). MS (ESI-), m / z: 226 [M−l] − Step 3
.깨끗하게 새로 준비한 6.8% (N¾)2S (22 L)에 상기 단계 2에서 제조된 2- 아미노 -3, 5-다이니트로 벤조산 (1.8 kg, 7.9 mol)을 첨가하였다. 상기 혼합물을 To the freshly prepared 6.8% (N¾) 2S (22 L) was added 2-amino-3, 5-dinitrobenzoic acid (1.8 kg, 7.9 mol) prepared in step 2 above. The mixture
90°C에서 2시간 동안 교반시킨 후 가열하여 여분의 암모니아를 제거하였다. 상온으로 식힌 후 고체로 형성된 황을 여과하여 제거하였다. 걸러진 여액을Stir at 90 ° C. for 2 hours and then remove excess ammonia by heating. After cooling to room temperature, the sulfur formed as a solid was removed by filtration. Filtered filtrate
5°C에서 초산으로 산성화시켜 생성된 고체를 여과하여 얻은 후 물로 세척하였다.The resulting solid obtained by acidification with acetic acid at 5 ° C. was filtered and washed with water.
75% 에탄올로 재결정하여 2 ,3-다이아미노 -5-니트로벤조산 (4) (1.1 kg)을 70¾> 수을로 얻었다. Recrystallization from 75% ethanol gave 2,3-diamino-5-nitrobenzoic acid (4) (1.1 kg) in 70¾> water.
5HNMR (400 MHz, DMS0_d6) δ： 8.07 (d, J = 3.2 Hz, 1H), 7.46 (d, J = 3.2 Hz, 1H), 7.45 (s, 2H). MS (ESI+) m/z: 198 [M+l]+ 5 HNMR (400 MHz, DMS0_d6) δ: 8.07 (d, J = 3.2 Hz, 1H), 7.46 (d, J = 3.2 Hz, 1H), 7.45 (s, 2H). MS (ESI +) m / z: 198 [M + l] &lt; + &gt;
B: 벤즈이미다졸 유도체의 제조 벤즈이미다졸 유도체들은 아래 반웅을 이용하여 합성되었다:
Figure imgf000059_0001
B: Preparation of Benzimidazole Derivatives Benzimidazole derivatives were synthesized using the following reactions:
Figure imgf000059_0001
2-메틸 -6-니트로 -1H-벤즈이미다졸 -4-카르복실산 2-Methyl-6-nitro-lH-benzimidazole-4-carboxylic acid
상기 A에서 제조된 2 ,3-다이아미노 -5-니트로벤조산 (600 mg, 3.05 隱 ol)을 초산 무수물 (7.0 mL)에 용해 시킨 후, 3N 염산 (20 mL)을 00C 에서 서서히 적가한 후 30분동안 환류 교반하였다. 상온으로 냉각시킨 후 고체를 여과하여 제거하였다. 여액을 감압농축한 후 수산화 나트륨 수용액 (0.5 N, 6 mL)에 용해시켰다. 상기 용액에 초산을 첨가하여 산성화시켜 생성된 고체를 감압 건조시켜 71% 수을 (480 mg)로 검은색의 고체 2-메틸 -6-니트로 -1H-벤즈이미다졸 -4-카르복실산을 얻었다. 상기 수득한 고체를 수회에 걸쳐 를루엔을 첨가 후 감압 제거하여 건조시켜 다음 반웅에 사용 하였다. 2,3-diamino-5-nitrobenzoic acid (600 mg, 3.05 μl ol) prepared in A was prepared After dissolving in acetic anhydride (7.0 mL), 3N hydrochloric acid (20 mL) was slowly added dropwise at 0 0 C, followed by stirring under reflux for 30 minutes. After cooling to room temperature, the solid was filtered off. The filtrate was concentrated under reduced pressure and then dissolved in an aqueous sodium hydroxide solution (0.5 N, 6 mL). The resulting solid was acidified by addition of acetic acid and the resulting solid was dried under reduced pressure to give a black solid 2-methyl-6-nitro-lH-benzimidazole-4-carboxylic acid as 71% aqueous (480 mg). The obtained solid was dried several times after the addition of toluene, followed by drying under reduced pressure.
匪 R (400 MHz, DMS0-d6) δ： 12.9 (s, 1H)， 8.58 (m, 1H), 8.53 (m, 1H), 2.61 (s, 3H). MS (ESI+) m/z: 222 [M+l]+ 실시예 1-3: 카보닐 아마이드유도체 카보닐 아마이드 유도체들은 아래 반웅을 이용하여 합성되었다. 匪 R (400 MHz, DMS0-d 6 ) δ: 12.9 (s, 1H), 8.58 (m, 1H), 8.53 (m, 1H), 2.61 (s, 3H). MS (ESI +) m / z: 222 [M + l] + Examples 1-3: Carbonyl Amide Derivatives Carbonyl amide derivatives were synthesized using the following reaction.
Figure imgf000060_0001
Figure imgf000060_0001
카르복실산을 MC와 테트라하이드로퓨란 (THF)의 4:1 (v/v) 용액에 흔합한 후 옥살릴 클로라이드 1.6당량을 적가하고 촉매량의 DMF를 적가하였다. 약 3시간정도 교반한 후 감압 농축하고 남은 물질을 다시 MC와 THF 4:l(v/v) 용액에 혼합한 후 일차 혹은 2차 아민을 적가 하였다. 상온에서 5시간 교반 후 물로 세척하고 무수 MgS 로 건조 후 감압 농축하였다. 이를 크로마토 그래피 법으로 분리하여 카보닐 아마이드 유도체를 얻었다. 상기 실시예 I을 이용하여， 각각에 상웅하는 출발물질을 이용하여 하기 표The carboxylic acid was mixed with a 4: 1 (v / v) solution of MC and tetrahydrofuran (THF), followed by the dropwise addition of 1.6 equivalents of oxalyl chloride and the catalytic amount of DMF. After stirring for about 3 hours, the mixture was concentrated under reduced pressure, and the remaining material was mixed with MC and THF 4: 1 (v / v) solution, and then primary or secondary amine was added dropwise. After stirring for 5 hours at room temperature, washed with water, dried over anhydrous MgS and concentrated under reduced pressure. This was separated by chromatography to obtain a carbonyl amide derivative. Using the above Example I, using the starting material to each of the following table
2에 기재된 실시예의 화합물을 제조하였다. 09 The compound of the Example described in 2 was prepared. 09
Figure imgf000061_0001
Figure imgf000061_0001
[Z Έ]  [Z Έ]
^6ΐ.00/ΐΐΟΖΗΜ/Χ3<Ι 060»0/ZI0Z OAV ¾ NMR (300 MHz, DMS0_d6) 12.28 (s, ^ 6ΐ.00 / ΐΐΟΖΗΜ / Χ3 <Ι 060 »0 / ZI0Z OAV ¾ NMR (300 MHz, DMS0_d 6 ) 12.28 (s,
[2-사이클로프로필 -6- 1H), 9.92 (s, 1H), 9.23 (s, 1H),  [2-cyclopropyl-6- 1H), 9.92 (s, 1H), 9.23 (s, 1H),
(8-메틸-퀴나졸린 -2- 8.53 (d, J=0.6 Hz, 1H), 7.70 (dd,  (8-methyl-quinazolin-2-8.53 (d, J = 0.6 Hz, 1H), 7.70 (dd,
76 일아미노) -1H- J=15.0, 7.2 Hz, 2H), 7.53 (s, 1H), 429.6 벤즈이미다졸 -4-일] - 7.26 (t, J=7.2 Hz, 1H), 3.67 (m,  76 ylamino) -1H-J = 15.0, 7.2 Hz, 2H), 7.53 (s, 1H), 429.6 benzimidazol-4-yl] -7.26 (t, J = 7.2 Hz, 1H), 3.67 (m,
모폴린 -4-일-메탄온 6H), 3.57 (m, 1H), 2.65 (s, 3H),  Morpholin-4-yl-methanone 6H), 3.57 (m, 1H), 2.65 (s, 3H),
2.09 (m, 1H), 1.04 (d, J=7.8 Hz, 4H)  2.09 (m, 1H), 1.04 (d, J = 7.8 Hz, 4H)
]H NMR (300 MHz, DMS0-d6)12.74 (s, ] H NMR (300 MHz, DMS0-d 6 ) 12.74 (s,
2-사이클로프로필 -6- 1H), 12.00 (s, 1H), 10.09 (s, 1H),  2-cyclopropyl-6- 1H), 12.00 (s, 1H), 10.09 (s, 1H),
(8-메틸-퀴나졸린 -2- 9.25 (s, 1H), 8.70 (s, 1H), 8.39 (s, 일아미노) -1H- (8-Methyl-quinazolin-2- 9.25 (s, 1H), 8.70 (s, 1H), 8.39 (s, monoamino) -1 H-
94 1H), 7.69 (m, 4H), 7.27 (t, J=8.1 520.5 벤즈이미다졸 -4- Hz, 1H), 6.99 (d, J=8.4 Hz, 2H), 94 1H), 7.69 (m, 4H), 7.27 (t, J = 8.1 520.5 benzimidazole-4-Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H),
카르복실산 (4-모폴린- 3.73 (s, 4H), 3.06 (s, 4H), 2.70  Carboxylic acid (4-morpholine-3.73 (s, 4H), 3.06 (s, 4H), 2.70
4-일—페닐) -아미드  4-yl—phenyl) -amide
(s, 3H), 2.43 (m' 1H), 1.17 (s, 4H)  (s, 3H), 2.43 (m '1H), 1.17 (s, 4H)
¾ NMR (300 MHz, DMS0-ds)10.07 (s, ¾ NMR (300 MHz, DMS0-d s ) 10.07 (s,
2-사이클로프로필 -6- 1H), 9.25 (s, 1H)ᅳ 8.69 (s, 1H),  2-cyclopropyl-6- 1H), 9.25 (s, 1H) ᅳ 8.69 (s, 1H),
(8-메틸-퀴나졸린 -2- 8.39 (s, 1H), 8.26 (brs, 1H), 7.73 일아미노) -1H- (dd, J=14.7, 7.8 Hz, 2H), 7.61 (d,  (8-methyl-quinazolin-2-8.39 (s, 1H), 8.26 (brs, 1H), 7.73 monoamino) -1H- (dd, J = 14.7, 7.8 Hz, 2H), 7.61 (d,
98 벤즈이미다졸 -4- 533.6  98 Benzimidazole-4-533.6
J=8.7 Hz, 2H), 7.27 (t, J=7.2 Hz,  J = 8.7 Hz, 2H), 7.27 (t, J = 7.2 Hz,
카르복실산 [4-(4- 1H), 6.98 (d, J=8.7 Hz, 2H)， 3.10  Carboxylic acid [4- (4- 1 H), 6.98 (d, J = 8.7 Hz, 2H), 3.10
메틸-피페라진 -1-일) - (m, 4H), 2.70 (s, 3H), 2.49 (m, 4H), 페닐] -아미드  Methyl-piperazin-1-yl)-(m, 4H), 2.70 (s, 3H), 2.49 (m, 4H), phenyl] -amide
2.21(ra 1H), 1.18 (d, J=8.4 Hz, 4H)  2.21 (ra 1H), 1.18 (d, J = 8.4 Hz, 4H)
2-사이클로프로필 -6- ¾ NMR (300 MHz, DMS으 d6) 12.77 (s, 2-cyclopropyl-6-¾ NMR (300 MHz, d 6 with DMS) 12.77 (s,
(8-메틸-퀴나졸린 -2- 1H), 12.17 (s, 1H), 10.08 (s, 1H),  (8-methyl-quinazolin-2-1H), 12.17 (s, 1H), 10.08 (s, 1H),
99 534.3 일아미노) -1H- 9.26 (s, 1H), 8.69 (d, J-1.8 Hz,  99 534.3 monoamino) -lH- 9.26 (s, 1H), 8.69 (d, J-1.8 Hz,
벤즈이미다졸 -4- 1H), 8.43 (d, J=1.8 Hz, 1H), 7.72 Z9 Benzimidazole-4-1H), 8.43 (d, J = 1.8 Hz, 1H), 7.72 Z9
Figure imgf000063_0001
Figure imgf000063_0001
^6lZ.00ll0ZaM/X3d 060»0/Π0Ζ OAV 3H), 2.49(m, 4H), 2.23(m, 4H), ^ 6lZ.00ll0ZaM / X3d 060 »0 / Π0Ζ OAV 3H), 2.49 (m, 4H), 2.23 (m, 4H),
]H NMR (300 MHz, DMS0, δ ) ： ] H NMR (300 MHz, DMS0, δ) ：
6-(8-메틸-퀴나졸린 -2- ll.OOCbr s, IH), 10.52(br s, IH), 일아미노) -1H- 9.35(s, IH), 9.12(br s, IH) , 8.53(br 벤조트리아졸 -4- s, IH), 7.82-7.76(m, 2H), 7.70(d, 카르복실산 (4-모폴린- J=9.0Hz, 2H), 7.35(t, J=7.2Hz, IH) , 4ᅳ일-페닐)—아미드 6.99(d, J=9.0Hz( 2H), 3.76-3.73(m, 6- (8-methyl-quinazolin-2-ll.OOCbr s, IH), 10.52 (br s, IH), monoamino) -1H-9.35 (s, IH), 9.12 (br s, IH), 8.53 (br benzotriazole-4-s, IH), 7.82-7.76 (m, 2H), 7.70 (d, carboxylic acid (4-morpholine-J = 9.0 Hz, 2H), 7.35 (t, J = 7.2 Hz, IH), 4 thyl-phenyl) —amide 6.99 (d, J = 9.0 Hz ( 2H), 3.76-3.73 (m,
4H), 3.10— 3.08 (m, 4H), 2.73(s, 3H) ' 4H), 3.10— 3.08 (m, 4H), 2.73 (s, 3H) ''
¾ NMR (300 MHz, DMS0-ds) 12.74 (s,¾ NMR (300 MHz, DMS0-d s ) 12.74 (s,
2-메틸— 6-(8-메틸- IH), 11.98 (s, IH), 10.10 (s, IH), 퀴나졸린 -2-일아미노) - 9.27 (s, IH), 8.75 (s, IH), 8.41 I 1H-벤즈이미다졸 -4- (s, IH), 7.72 (m, 4H), 7.28 (t, 카르복실산 (4-모폴린- J=7.2 Hz, IH), 6.98 (d, J=9.3 Hz, 4-일-페닐) -아미드 2H), 3.74 (s, 4H), 3.08 (s, 4H), 2-methyl- 6- (8-methyl-IH), 11.98 (s, IH), 10.10 (s, IH), quinazolin-2-ylamino)-9.27 (s, IH), 8.75 (s, IH) , 8.41 I 1 H-benzimidazole-4- (s, IH), 7.72 (m, 4H), 7.28 (t, carboxylic acid (4-morpholine- J = 7.2 Hz, IH), 6.98 (d, J = 9.3 Hz, 4-yl-phenyl) -amide 2H), 3.74 (s, 4H), 3.08 (s, 4H),
2.70 (s, 3H), 2.63 (s, 3H)  2.70 (s, 3H), 2.63 (s, 3H)
¾匪 R (300 MHz, DMS0-ds) 12.77 (s,¾ 匪 R (300 MHz, DMS0-d s ) 12.77 (s,
2-메틸 -6-(8-메틸- IH), 12.20 (s, IH), 10.11 (s, IH), 퀴나졸린 -2-일아미노) - 9.27 (s, IH), 8.77 (s, IH), 8.42 (s I 1H-벤즈이미다졸 -4- IH), 7.72 (m, 4H), 7.30 (m, 3H), 카르복실산 (4-모폴린- 3.57 (m, 4H), 3.44 (s, 2H), 2.70 (s 4-일메틸-페닐) -아미드 2-methyl-6- (8-methyl-IH), 12.20 (s, IH), 10.11 (s, IH), quinazolin-2-ylamino) -9.27 (s, IH), 8.77 (s, IH) , 8.42 (s I 1 H-benzimidazole-4-IH), 7.72 (m, 4H), 7.30 (m, 3H), carboxylic acid (4-morpholine-3.57 (m, 4H), 3.44 (s, 2H), 2.70 (s 4-ylmethyl-phenyl) -amide
2H), 2.64 (s, 3H), 2.35 (s, 3H) 2H), 2.64 (s, 3H), 2.35 (s, 3H)
2-이소프로필 -6- (8- ]H NMR (300 MHz, DMS0— d6) 10.21 (brs, 메틸-퀴나졸린 -2- IH), 9.31 (s, IH), 8.69 (s, IH), 일아미노) -1H- 8.69 (brs, IH), 7.72 (m, 4H), 7.51 벤즈이미다졸 -4- (t, J=7.2 Hz, IH), 7.01 (d, J=8.7 카르복실산 (4-모폴린- Hz, 2H), 3.75 (t, J =4.5 Hz, 4H), 2-isopropyl-6- (8- ) H NMR (300 MHz, DMS0—d 6 ) 10.21 (brs, methyl-quinazolin-2-IH), 9.31 (s, IH), 8.69 (s, IH), Monoamino) -1H-8.69 (brs, IH), 7.72 (m, 4H), 7.51 benzimidazole-4- (t, J = 7.2 Hz, IH), 7.01 (d, J = 8.7 carboxylic acid (4 -Morpholine- Hz, 2H), 3.75 (t, J = 4.5 Hz, 4H),
Figure imgf000065_0001
?6ΐ.00/ΙΙΟΖΗΜ/Χ3<Ι 060»0/Π0Ζ OAV [4-(2,2,2- J=7.8Hz, 1H), 3.66(m, 2H), 3.20(m, 트리플루오로-에틸) - 2H), 2.70-2.64(m, 6H), 2.10(m, 1H), 피페라진 -1-일] -메탄온 1.03(m, 4H)
Figure imgf000065_0001
? 6ΐ.00 / ΙΙΟΖΗΜ / Χ3 <Ι 060 »0 / Π0Ζ OAV (4- (2,2,2-J = 7.8 Hz, 1H), 3.66 (m, 2H), 3.20 (m, trifluoro-ethyl) -2H), 2.70-2.64 (m, 6H), 2.10 ( m, 1H), piperazin-1-yl] -methanone 1.03 (m, 4H)
¾ NMR (300 MHz, DMS0-ds) 10.33 (br ¾ NMR (300 MHz, DMS0-d s ) 10.33 (br
2-사이클로프로필 -6- s, 1H), 9.37 (d, J=5.1Hz, 1H), 8.81  2-cyclopropyl-6-s, 1H), 9.37 (d, J = 5.1 Hz, 1H), 8.81
(8-메틸-퀴나졸린 -2- (br s, 1H), 8.68 (s, 1H), 8.63 (s, 일아미노) -1H- 1H), 8.14 (d, J =8.7Hz, 1H)， 7.82  (8-Methyl-quinazolin-2- (br s, 1H), 8.68 (s, 1H), 8.63 (s, monoamino) -1H-1H), 8.14 (d, J = 8.7 Hz, 1H), 7.82
120 벤즈이미다졸 -4- (d, J=7.8Hz,， 1H), 7.75 (d, J=6.0 521 카르복실산 (6-모폴린- Hz, 1H), 7.34(t, J=7.5 Hz, 1H), 7.15  120 benzimidazole-4- (d, J = 7.8 Hz, 1H), 7.75 (d, J = 6.0 521 carboxylic acid (6-morpholine-Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.15
4-일-피리딘 -3ᅳ일) - (d, J=8.7 Hz, 1H), 3.75 (m, 4H),  4-yl-pyridine-3 ylyl)-(d, J = 8.7 Hz, 1H), 3.75 (m, 4H),
아미드 3.53 (m, 4H), 2.70 (s, 3H), 2.47 (m,  Amide 3.53 (m, 4H), 2.70 (s, 3H), 2.47 (m,
1H), 1.47 (m,4H)  1H), 1.47 (m, 4H)
¾ NMR (300 MHz, DMSO— d6) 12.78 (s, ¾ NMR (300 MHz, DMSO— d 6 ) 12.78 (s,
1H), 12.49 (s, 1H), 10.66 (brs,  1H), 12.49 (s, 1H), 10.66 (brs,
2-이소프로필 -6-(8- 1H), 10.15 (s, 1H), 9.28 (s, 1H),  2-isopropyl-6- (8-1H), 10.15 (s, 1H), 9.28 (s, 1H),
메틸-퀴나졸린 -2- 8.74 (s, 1H), 8.48 (s, 1H), 8.10 (s, 일아미노) -1H- 1H), 7.75 (d, J=7.8 Hz, 1H), 7.70  Methyl-quinazolin-2-8.74 (s, 1H), 8.48 (s, 1H), 8.10 (s, monoamino) -1H-1H), 7.75 (d, J = 7.8 Hz, 1H), 7.70
121 536.4 벤즈이미다졸 -4- (d, J=6.9 Hz, 1H), 7.51 (t, J=7.8  121 536.4 Benzimidazole-4- (d, J = 6.9 Hz, 1H), 7.51 (t, J = 7.8
카르복실산 (3-모폴린- Hz, 1H), 7.31 (m, 2H), 4.39 (brs,  Carboxylic acid (3-morpholine- Hz, 1H), 7.31 (m, 2H), 4.39 (brs,
4-일메틸-페닐) -아미드 2H), 3.94 (d, J=ll.l Hz, 2H), 3.72  4-ylmethyl-phenyl) -amide 2H), 3.94 (d, J = ll.l Hz, 2H), 3.72
(t, J=ll.l Hz, 2H), 3.15 (m, 4H),  (t, J = ll.l Hz, 2H), 3.15 (m, 4H),
2.72 (s, 3H), 1.47 (d, J=6.9 Hz, 6H)  2.72 (s, 3H), 1.47 (d, J = 6.9 Hz, 6H)
2-메틸— 6-(8-메틸- ]H NMR (300 MHz, DMS0-ds) 12.78 (brs, 2-methyl- 6- (8-methyl- ] H NMR (300 MHz, DMS0-d s ) 12.78 (brs,
122 퀴나졸린 -2—일아미노) - 1H), 12.21 (s, 1H), 10.11 (s, 1H), 508.3 1H-벤즈이미다졸 -4- 9.27 (s, 1H), 8.78 (s, 1H), 8.40 카르복실산 (3-모폴린- (s, 1H), 7.74 (d, J=6.9 Hz, 2H), 122 Quinazolin-2—ylamino) -1H), 12.21 (s, 1H), 10.11 (s, 1H), 508.3 1H-benzimidazole-4- 9.27 (s, 1H), 8.78 (s, 1H), 8.40 Carboxylic acid (3-morpholine- (s, 1H), 7.74 (d, J = 6.9 Hz, 2H),
4-일메틸-페닐)—아미드 7.70 (d, J-7.2 Hz, 2H), 7.31 (s,  4-ylmethyl-phenyl) -amide 7.70 (d, J-7.2 Hz, 2H), 7.31 (s,
IH), 7.06 (d, J=7.2 Hz, IH), 3.59  IH), 7.06 (d, J = 7.2 Hz, IH), 3.59
(t, J=4.5 Hz, 4H), 3.49 (s, 2H),  (t, J = 4.5 Hz, 4H), 3.49 (s, 2H),
2.67 (d, J=18.6 Hz, 3H), 2.55 (d,  2.67 (d, J = 18.6 Hz, 3H), 2.55 (d,
J=1.5 Hz, 3H), 2.39 (t, J=4.5 Hz,  J = 1.5 Hz, 3H), 2.39 (t, J = 4.5 Hz,
4H)  4H)
¾ NMR (300 MHz, DMS으 d6) 9.91 (s, ¾ NMR (300 MHz, d 6 with DMS) 9.91 (s,
4']바이피페리딘일- IH), 9.24 (s, IH), 8.57 (s, IH),  4 '] bipiperidinyl- IH), 9.24 (s, IH), 8.57 (s, IH),
Γ-일 -[2-메틸 -6-(8- 8.13 (s, IH), 7.70 (dd, J=15.6, 7.5 메틸-퀴나졸린 -2- Γ-yl-[2-methyl-6- (8-8.13 (s, IH), 7.70 (dd, J = 15.6, 7.5 methyl-quinazolin-2-
125 Hz, 2H), 7.52 (s, IH), 7.25 (t, 484.2 일아미노)— 1H- J=7.5 Hz, IH), 4.66 (brs, IH), 3.57 벤즈이미다졸 -4-일] - (brs, 2H), 2.85 (m, 6H) , 2.77 (s, 125 Hz, 2H), 7.52 (s, IH), 7.25 (t, 484.2 ylamino) — 1H- J = 7.5 Hz, IH), 4.66 (brs, IH), 3.57 benzimidazol-4-yl]-( brs, 2H), 2.85 (m, 6H), 2.77 (s,
메탄온  Methanone
3H), 2.63 (s, 3H), 1.58 (m, IH)  3H), 2.63 (s, 3H), 1.58 (m, IH)
Ή NMR (300 MHz, DMSO, δ ) ：  NMR (300 MHz, DMSO, δ):
2-사이클로프로필 -6- 9.79(sᅳ 1Η)' 9.75(d, J=7.2Hz, IH),  2-cyclopropyl -6- 9.79 (s ᅳ 1Η) '9.75 (d, J = 7.2 Hz, IH),
(8-메틸-퀴나졸린 -2- 8.20(s, IH), 8.11(d, J=7.8Hz, IH),  (8-methyl-quinazolin-2-8.20 (s, IH), 8.11 (d, J = 7.8 Hz, IH),
일아미노) -1H- 7.97(d, J=6.9Hz, IH), 7.70(t,  Monoamino) -1H-7.97 (d, J = 6.9 Hz, IH), 7.70 (t,
138 벤즈이미다졸 -4- 484.2  138 Benzimidazole-4- 484.2
J=6.9Hz, IH), 7.49(s, IH), 7.27(s,  J = 6.9 Hz, IH), 7.49 (s, IH), 7.27 (s,
카르복실산 (1- IH), 3.94(m, 2H), 3.02(m, IH), 2.84- 이소프로필-피페리딘- 2.78(m, 2H), 1.96(m, 2H), 1.57(m,  Carboxylic acid (1-IH), 3.94 (m, 2H), 3.02 (m, IH), 2.84-isopropyl-piperidine-2.78 (m, 2H), 1.96 (m, 2H), 1.57 (m,
4-일) -아미드  4-yl) -amide
2H), 1.51-1.24(m, 4H),  2H), 1.51-1.24 (m, 4H),
[2-사이클로프로필 -6- ¾ NMR (300 MHz, DMSO, δ ) ：  [2-cyclopropyl-6-¾ NMR (300 MHz, DMSO, δ) ：
(8-메틸-퀴나졸린 -2- 9.90(s, IH), 9.23(s, IH), 8.46(s,  (8-methyl-quinazolin-2- 9.90 (s, IH), 9.23 (s, IH), 8.46 (s,
146 470.1 일아미노) -1H- IH), 8.14(s, IH), 7.73-7.66 (m, 2H), 벤즈이미다졸 -4-일] - 7.58(br s, IH), 7.25(t, J-7.8Hz, (4-이소프로필- IH), 3.67(m, 2H), 3.22(m, 2H), 2.75- 피페라진 -1-일) -메탄온 2.66(m, IH), 2.64(s, 3H), 2.52(m, 146 470.1 ylamino) -1H-IH), 8.14 (s, IH), 7.73-7.66 (m, 2H), benzimidazol-4-yl] -7.58 (br s, IH), 7.25 (t, J- 7.8 Hz, (4-isopropyl-IH), 3.67 (m, 2H), 3.22 (m, 2H), 2.75-piperazin-1-yl) -methanone 2.66 (m, IH), 2.64 (s, 3H), 2.52 (m,
4H), 2.10(m, IH), 1.03(m, 4H), 0.97(d, J=6.3Hz, 6H)  4H), 2.10 (m, IH), 1.03 (m, 4H), 0.97 (d, J = 6.3 Hz, 6H)
¾ NMR (300 MHz, DMS0, δ ) ：  ¾ NMR (300 MHz, DMS0, δ) ：
9.92(s, IH), 9.26(s, IH), 8.58(s, 9.92 (s, IH), 9.26 (s, IH), 8.58 (s,
[2-메틸 -6-(8-메틸- IH), 8.16(s, 2H), 7.76(d, J=8.1Hz, 퀴나졸린 -2-일아미노) - IH), 7.71(d, J=6.6Hz, IH), 7.57(s, I 1H-벤즈이미다졸 -4- IH), 7.28(t, J=7.2Hz, 1H)' 4.60(br, 일] -(4-모폴린 -4-일- IH), 3.58(br, 4H), 2.90(br, 2H), 피페리딘 -1-일) -메탄온 [2-Methyl-6- (8-methyl-IH), 8.16 (s, 2H), 7.76 (d, J = 8.1 Hz, quinazolin-2-ylamino) -IH), 7.71 (d, J = 6.6 Hz, IH), 7.57 (s, I 1 H-benzimidazole-4-IH), 7.28 (t, J = 7.2 Hz, 1H) ' 4.60 (br, day)-(4-morpholin-4-yl- IH), 3.58 (br, 4H), 2.90 (br, 2H), piperidin-1-yl) -methanone
2.66, (s, 3H), 2.66(m, IH), 2.50(m, 7H), 1.80(Br, 2H),1.42(m, 2H) 2.66, (s, 3H), 2.66 (m, IH), 2.50 (m, 7H), 1.80 (Br, 2H), 1.42 (m, 2H)
¾ NMR (300 MHz, DMS0, δ ) ： ¾ NMR (300 MHz, DMS0, δ) ：
[2-사이클로프로필 -6- 9.91(s, IH), 9.25(s, IH), 8.50(s, (8-메틸-퀴나졸린 -2- IH), 8.16(s, 2H), 7.76(d, J=7.8Hz, 일아미노)— 1H- IH), 7.70(d, J=7.2Hz, IH), 7.58(s, [2-cyclopropyl-6- 9.91 (s, IH), 9.25 (s, IH), 8.50 (s, (8-methyl-quinazolin-2-IH), 8.16 (s, 2H), 7.76 (d, J = 7.8 Hz, monoamino) — 1H-IH), 7.70 (d, J = 7.2 Hz, IH), 7.58 (s,
148 148
벤즈이미다졸 -4-일] - IH), 7.27(t, J=7.5Hz, IH)， 4.60(br, (4-모폴린 -4-일- IH), 3.58(br, 4H), 2.89(br, 2H), 피페리딘 -1-일) -메탄은 2.66, (s, 3H), 2.15(m, IH), 1.80(Br,  Benzimidazol-4-yl] -IH), 7.27 (t, J = 7.5 Hz, IH), 4.60 (br, (4-morpholin-4-yl-IH), 3.58 (br, 4H), 2.89 ( br, 2H), piperidin-1-yl) -methane is 2.66, (s, 3H), 2.15 (m, IH), 1.80 (Br,
2H),1.45(m, 2H), 1.07(m, 4H)  2H), 1.45 (m, 2H), 1.07 (m, 4H)
[2-이소프로필 -6-(8- ¾ NMR (300 MHz, DMS0, δ ) ： 메틸-퀴나졸린 -2— 9.93(s, IH), 9.26(s, IH), 8.56(s, 일아미노) -1H- IH), 8.16(s, 2H), 7.76(d, J=8.1Hz, [2-isopropyl-6- (8-¾ NMR (300 MHz, DMS0, δ): Methyl-quinazolin-2—9.93 (s, IH), 9.26 (s, IH), 8.56 (s, monoamino) -1H-IH), 8.16 (s, 2H), 7.76 (d, J = 8.1 Hz,
149 149
벤즈이미다졸 -4-일] - IH), 7.71(d, J=8.2Hz, IH), 7.57(s, (4-모플린 -4-일- IH), 7.28(t, J =8.4Hz, IH)ᅳ 4.58(br, 피페리딘 -1-일) -메탄온 IH), 3.57(br, 4H), 3.20(m, 6H), 2.89(br, 2H), 2.67, (s, 3H), 2.50(m, Benzimidazol-4-yl] -IH), 7.71 (d, J = 8.2 Hz, IH), 7.57 (s, (4-morpholin-4-yl-IH), 7.28 (t, J = 8.4 Hz, IH) ᅳ 4.58 (br, piperidin-1-yl) -methanone IH), 3.57 (br, 4H), 3.20 (m, 6H), 2.89 (br, 2H), 2.67, (s, 3H), 2.50 (m,
1.89(br, 2H),1.45(m, 2H), 1.37(d,  1.89 (br, 2H), 1.45 (m, 2H), 1.37 (d,
J=6.6Hz, 6H)  J = 6.6Hz, 6H)
2-사이클로프로필 -6- ¾ NMR (300 MHz, DMS0_d6) 12.02 (s, 2-cyclopropyl-6-¾ NMR (300 MHz, DMS0_d 6 ) 12.02 (s,
(8-메틸-퀴나졸린 -2- IH), 9.81 (brs, IH), 9.20 (s, IH), 일아미노) -1H- 8.16 (s, IH), 7.68 (dd, J=15.3, 8.4  (8-methyl-quinazolin-2-IH), 9.81 (brs, IH), 9.20 (s, IH), monoamino) -1H-8.16 (s, IH), 7.68 (dd, J = 15.3, 8.4
152 벤즈이미다졸 -4- Hz, 2H), 7.47 (s, IH), 7.24 (t， 548.4 카르복실산 메틸— (4- J=7.2 Hz, IH), 7.08 (brs, 4H), 3.25 모폴린 -4-일메틸- Cm, 9H), 2.61 (s, 3H) , 2.12 (m,  152 benzimidazole-4- Hz, 2H), 7.47 (s, IH), 7.24 (t, 548.4 methyl carboxylic acid— (4- J = 7.2 Hz, IH), 7.08 (brs, 4H), 3.25 morpholine -4-ylmethyl-Cm, 9H), 2.61 (s, 3H), 2.12 (m,
페닐) -아미드 5H), 0.99 (d, J=8.1 Hz, 4H)  Phenyl) -amide 5H), 0.99 (d, J = 8.1 Hz, 4H)
¾ NMR (300 MHz, DMS0-d6) 9.88 (s, ¾ NMR (300 MHz, DMS0-d 6 ) 9.88 (s,
2-사이클로프로필 -6- IH), 9.23 (s, IH), 8.50 (brs, IH),  2-cyclopropyl-6-IH), 9.23 (s, IH), 8.50 (brs, IH),
(8-메틸-퀴나졸린 -2- 8.32 (s, IH), 7.69 (dd, J=16.2, 8.1 일아미노) -1H- Hz, 2H), 7.42 (brs, IH) , 7.25 (t,  (8-Methyl-quinazolin-2- 8.32 (s, IH), 7.69 (dd, J = 16.2, 8.1 monoamino) -1H- Hz, 2H), 7.42 (brs, IH), 7.25 (t,
153 벤즈이미다졸 -4- 456.2  153 Benzimidazole-4-456.2
J=7.5 Hz, IH), 3.55 (m, 4H), 2.97  J = 7.5 Hz, IH), 3.55 (m, 4H), 2.97
카르복실산 메틸ᅳ (1- (s, 3H), 2.63 (s, 3H), 2.14 (m,  Methyl carboxylate (1- (s, 3H), 2.63 (s, 3H), 2.14 (m,
메틸-피를리딘 -3-일) - 6H), 1.80 Cm, IH), 1.02 (d, J=8.4  Methyl-pyridin-3-yl) -6H), 1.80 Cm, IH), 1.02 (d, J = 8.4
아미드  amides
Hz, 4H)  Hz, 4H)
2-사이클로프로필 -6- ¾ NMR (300 MHz, DMS0_d6) 9.70 (brs, 2-cyclopropyl-6-¾ NMR (300 MHz, DMS0_d 6 ) 9.70 (brs,
(8-메틸—퀴나졸린 -2- IH), 9.19 (s, IH), 8.34 (brs, IH),  (8-methyl-quinazolin-2-IH), 9.19 (s, IH), 8.34 (brs, IH),
일아미노) -1H- 8.18 (s, IH), 7.67 (dd, J=15.0, 8.1  Monoamino) -1H-8.18 (s, IH), 7.67 (dd, J = 15.0, 8.1
156 벤즈이미다졸 -4- Hz, 2H), 7.37 (s, IH), 7.23 (t, 589.3 카르복실산 [4-(4- J-7.2 Hz, IH), 7.06 (m, 4H) , 3.28  156 benzimidazole-4-Hz, 2H), 7.37 (s, IH), 7.23 (t, 589.3 carboxylic acids [4- (4-J-7.2 Hz, IH), 7.06 (m, 4H), 3.28
이소프로필-피페라진- On, 3H), 3.14 (m, 3H), 2.61 (s, 3H),  Isopropyl-piperazine- On, 3H), 3.14 (m, 3H), 2.61 (s, 3H),
1-일메틸) -페닐] -메틸- 2.21 (m, 6H), 0.98 (d, J=7.8 Hz, 아미드 4H), 0.80 (d, J=5.4 Hz, 6H) 1-ylmethyl) -phenyl] -methyl-2.21 (m, 6H), 0.98 (d, J = 7.8 Hz, Amide 4H), 0.80 (d, J = 5.4 Hz, 6H)
¾ NMR (300 MHz, DMS0-d6) 9.73 (brs, ¾ NMR (300 MHz, DMS0-d 6 ) 9.73 (brs,
2-메틸 -6-(8-메틸- 1H), 9.20 (s, 1H), 8.42 (s, 1H),  2-methyl-6- (8-methyl-1H), 9.20 (s, 1 H), 8.42 (s, 1 H),
퀴나졸린 -2-일아미노) - 8.13 (s, 1H), 7.68 (dd, J=14.7, 8.1  Quinazolin-2-ylamino)-8.13 (s, 1H), 7.68 (dd, J = 14.7, 8.1
1H-벤즈이미다졸 -4- Hz, 2H), 7.40 (brs, 1H), 7.24 (t,  1H-benzimidazole-4-Hz, 2H), 7.40 (brs, 1H), 7.24 (t,
160 522.3 카르복실산 메틸 -(4- J=6.9 Hz, 1H), 7.10 (m, 4H), 3.26  160 522.3 Methyl Carboxylic Acid- (4- J = 6.9 Hz, 1H), 7.10 (m, 4H), 3.26
모폴린 -4-일메틸- (m, 6H), 3.15 (d, J=1.2 Hz, 3H),  Morpholin-4-ylmethyl- (m, 6H), 3.15 (d, J = 1.2 Hz, 3H),
페닐) -아미드 2.61 (s, 3H), 2.42 (s, 3H), 2.14 (m,  Phenyl) -amide 2.61 (s, 3H), 2.42 (s, 3H), 2.14 (m,
4H)  4H)
¾ NMR (300 MHz, DMS0-d6) 12.12 ¾ NMR (300 MHz, DMS0-d 6 ) 12.12
6-(8ᅳ클로로-퀴나졸린- (brs, 1H), 10.01 (brs, 1H), 9.30 (s,  6- (8 ᅳ chloro-quinazolin- (brs, 1H), 10.01 (brs, 1H), 9.30 (s,
2-일아미노) -2-메틸- 1H), 8.57 (brs, 1H), 8.14 (s, 1H),  2-ylamino) -2-methyl-1H), 8.57 (brs, 1H), 8.14 (s, 1H),
1H-벤즈이미다졸 -4— 7.97 (d, J=7.8 Hz, 1H), 7.87 (d,  1H-benzimidazole-4—7.97 (d, J = 7.8 Hz, 1H), 7.87 (d,
167 543.2 카르복실산 메될 -(4- J=6.9 Hz, 2H), 7.32 (t, J=7.8 Hz,  167 543.2 carboxylic acid mezyl- (4-J = 6.9 Hz, 2H), 7.32 (t, J = 7.8 Hz,
모폴린 -4-일메틸- 1H), 7.10 (m, 4H), 3.26 (m, 6H),  Morpholin-4-ylmethyl-1H), 7.10 (m, 4H), 3.26 (m, 6H),
페닐) -아미드 3.15 (s, 3H), 2.42 (s, 3H), 2.14 (m,  Phenyl) -amide 3.15 (s, 3H), 2.42 (s, 3H), 2.14 (m,
4H)  4H)
]H NMR (300 MHz, DMS0-ds) 12.07 (s, ] H NMR (300 MHz, DMS0-d s ) 12.07 (s,
2-메틸 -6-(8-메틸- 1H), 9.69 (s, 1H), 9.19 (s, 1H),  2-methyl-6- (8-methyl-1H), 9.69 (s, 1 H), 9.19 (s, 1 H),
퀴나졸린 -2-일아미노) - 8.41 (s, 1H), 7.68 (m, 2H), 7.23 (m,  Quinazolin-2-ylamino)-8.41 (s, 1H), 7.68 (m, 2H), 7.23 (m,
1H-벤즈이미다졸 -4- 2H), 7.03 (d, J-9.0 Hz, 2H) , 6.71  1H-benzimidazole-4-2H), 7.03 (d, J-9.0 Hz, 2H), 6.71
168 508.1 카르복실산 메틸— (4- (d, J=8.7 Hz, 1H), 6.65 (brs, 1H),  168 508.1 Methyl Carboxylic Acid— (4- (d, J = 8.7 Hz, 1H), 6.65 (brs, 1H),
모폴린 -4-일-페닐) - 3.59 (m, 4H), 3.35 (s, 3H), 2.93 (m, 아미드 4H), 2.62 (d, J=9.6 Hz, 3H), 2.43  Morpholin-4-yl-phenyl) -3.59 (m, 4H), 3.35 (s, 3H), 2.93 (m, amide 4H), 2.62 (d, J = 9.6 Hz, 3H), 2.43
(s, 3H) ¾ 匪 R (300 MHz, DMS0-d6) 12.37 (s, (s, 3H) ¾ 匪 R (300 MHz, DMS0-d 6 ) 12.37 (s,
1H), 9.95 (s, 1H), 9.24 (s, 1H); 1H), 9.95 (s, 1 H), 9.24 (s, 1 H) ;
[4-(4-플루오로-페닐) - 8.57 (s, 1H), 7.70 (dd, J=17.0, 7.3 피페라진 -1-일] -[2- Hz, 3H), 7.56 (s, 1H), 7.26 (t,  [4- (4-Fluoro-phenyl) -8.57 (s, 1 H), 7.70 (dd, J = 17.0, 7.3 piperazin-1-yl]-[2- Hz, 3 H), 7.56 (s, 1 H) , 7.26 (t,
메틸 -6-(8-메틸- Methyl-6- (8-methyl-
170 1=7 A Hz, 1H), 7.04 (t, 1=8.7 Hz, 496.2 퀴나졸린 -2ᅳ일아미노) - 2H), 6.97 (d, 1=4.5 Hz, 2H)， 3.83 170 1 = 7 A Hz, 1H), 7.04 (t, 1 = 8.7 Hz, 496.2 quinazoline-2xylamino) -2H), 6.97 (d, 1 = 4.5 Hz, 2H), 3.83
1H-벤즈이미다졸 -4- Cm, 2H), 3.36 On, 2H), 3.17 (m,  1H-benzimidazole-4-Cm, 2H), 3.36 On, 2H), 3.17 (m,
일] -메탄온  Day] -methanone
2H), 3.03 (m, 2H), 2.62 (d, J=7.8  2H), 3.03 (m, 2H), 2.62 (d, J = 7.8
Hz, 3H), 2.46 (s, 3H)  Hz, 3H), 2.46 (s, 3H)
]H NMR (300 MHz, DMSO, δ ) ： ] H NMR (300 MHz, DMSO, δ) ：
[6-(8-메틸 -퀴나졸린ᅳ 13.16(s, 1H), 10.19(s, 1H), 9.31(s,  [6- (8-Methyl-quinazolinline 13.16 (s, 1H), 10.19 (s, 1H), 9.31 (s,
2-일아미노) -1H- 1H), 8.78(s, 1H), 7.93(s, 1H), 7.79- 2-ylamino) -1H-1H), 8.78 (s, 1H), 7.93 (s, 1H), 7.79-
171 389.1 인다졸 -4-일] -모폴린- 7.71(ra, 2H), 7.51(s, 1H), 7.33(t, 171 389.1 indazol-4-yl] -morpholine- 7.71 (ra, 2H), 7.51 (s, 1H), 7.33 (t,
4-일-메탄온 J=7.5Hz, 1H), 3.61(m, 8H), 2.70(s,  4-yl-methanone J = 7.5 Hz, 1H), 3.61 (m, 8H), 2.70 (s,
3H)  3H)
!H NMR (300 MHz, DMSOd6) 12.28 (s, ! H NMR (300 MHz, DMSOd 6 ) 12.28 (s,
1H), 9.94 (s, 1H), 9.24 (s, 1H),  1H), 9.94 (s, 1H), 9.24 (s, 1H),
[2-사이클로프로필 -6- 8.53 (s, 1H), 7.73 (m, 2H), 7.56 (s,  [2-cyclopropyl-6-8.53 (s, 1H), 7.73 (m, 2H), 7.56 (s,
(8-메틸-퀴나졸린 -2- 1H), 7.25 (t, J=7.5 Hz, 1H), 7.05  (8-methyl-quinazolin-2-1H), 7.25 (t, J = 7.5 Hz, 1H), 7.05
일아미노) -1H- Monoamino) -1H-
172 (t, J=8.7 Hz, 2H), 6.97 (d, J=4.8 522.2 벤즈이미다졸 -4-일] - Hz, 1H)( 3.82 (m, 2H), 3.32 (m, 172 (t, J = 8.7 Hz, 2H), 6.97 (d, J = 4.8 522.2 benzimidazol-4-yl] -Hz, 1H) ( 3.82 (m, 2H), 3.32 (m,
[4ᅳ (4-플루오로-페닐) - 2H), 3.16 (m, 2H), 3.06 (m, 2H) ,  [4 '(4-Fluoro-phenyl) -2H), 3.16 (m, 2H), 3.06 (m, 2H),
피페라진 -1-일] -메탄온  Piperazine-1-yl] -methanone
2.64 (s, 3H), 2.11 (m, 1H), 1.02 (d,  2.64 (s, 3 H), 2.11 (m, 1 H), 1.02 (d,
J=8.4 Hz, 4H) IL J = 8.4 Hz, 4H) IL
Figure imgf000072_0001
Figure imgf000072_0001
^6ΐ.00/ΐΐΟΖΗΜ/Χ3<Ι 060»0/ΖΪ0Ζ OAV ¾ 匿 (300 MHz, DMS0, δ ) ： ^ 6ΐ.00 / ΐΐΟΖΗΜ / Χ3 <Ι 060 »0 / ΖΪ0Ζ OAV ¾ 匿 (300 MHz, DMS0, δ) ：
[2-에틸 -6-(8-메틸- 10.29(s, 1H), 9.32(s, 1H), 9.07(s,  [2-ethyl-6- (8-methyl-10.29 (s, 1H), 9.32 (s, 1H), 9.07 (s,
퀴나졸린 -2-일아미노) - 1H), 7.92(s, 1H), 7.80-7.72 (ra, 2H) ,  Quinazolin-2-ylamino) -1H), 7.92 (s, 1H), 7.80-7.72 (ra, 2H),
176 417.3 2H-인다졸 4ᅳ일] - 7.37—7.30(iii, 2H), 4.43(q, J=7.5Hz,  176 417.3 2H-indazol 4minyl]-7.37—7.30 (iii, 2H), 4.43 (q, J = 7.5 Hz,
모폴린 -4-일-메탄은 2H), 3.62(m, 4H), 3.34(m, 4H),  Morpholin-4-yl-methane is 2H), 3.62 (m, 4H), 3.34 (m, 4H),
2.71(s, 3H), 1.45'(t, J=7.5Hz, 3H) 2.71 (s, 3H), 1.45 ' (t, J = 7.5Hz, 3H)
¾ 薩 R (300 MHz, DMSO, δ ) ：  ¾ 薩 R (300 MHz, DMSO, δ) ：
10.03(s, 1H), 9.28(s, 1H), 8.82(s,  10.03 (s, 1H), 9.28 (s, 1H), 8.82 (s,
[1-에틸-6-(8-메틸- 1H), 8.30(s, 1H), 7.77-7.69(m, 2H),  [1-ethyl-6- (8-methyl-1H), 8.30 (s, 1 H), 7.77-7.69 (m, 2H),
퀴나졸린 -2-일아미노) - Quinazolin-2-ylamino)-
177 7.42(s, 1H), 7.29(t, J=7.5Hz, 1H), 417.3 1H-인다졸 -4-일] - 4.41(q, J=7.5Hz, 2H), 3.62-3.51(m, 177 7.42 (s, 1 H), 7.29 (t, J = 7.5 Hz, 1 H), 417.3 1 H-indazol-4-yl]-4.41 (q, J = 7.5 Hz, 2H), 3.62-3.51 (m,
모폴린 -4-일-메탄온  Morpholin-4-yl-methanone
8H), 2.67(s, 3H), 1.49(t, J=7.2Hz,  8H), 2.67 (s, 3H), 1.49 (t, J = 7.2 Hz,
3H)  3H)
¾ 匪 R (300 MHz, DMSO, δ ) ：  ¾ 匪 R (300 MHz, DMSO, δ) ：
1-에틸 -6-(8-메틸- 10.38(s, 1H), 10.05(s, 1H), 9.30(s,  1-ethyl-6- (8-methyl-10.38 (s, 1H), 10.05 (s, 1H), 9.30 (s,
퀴나졸린 -2-일아미노) - 1H), 8.74(s, 1H), 8.48(s, 1H),  Quinazolin-2-ylamino) -1H), 8.74 (s, 1H), 8.48 (s, 1H),
1H-인다졸 -4- 8.14(s, 1H), 7.78-7.69(m, 2H), 7.33- 1H-indazol-4-8.14 (s, 1H), 7.78-7.69 (m, 2H), 7.33-
182 526.2 카르복실산 (3- 7.18(m, 3H), 6.56-6.52(m, 1H), 182 526.2 carboxylic acid (3- 7.18 (m, 3H), 6.56-6.52 (m, 1H),
플루오로 -5-모폴린 -4- 4.45(q, J=7.5Hz, 2H), 3.73(m, 4H),  Fluoro-5-morpholine-4-4.45 (q, J = 7.5 Hz, 2H), 3.73 (m, 4H),
일-페닐) -아미드 3.12(m, 4H), 2.65(s, 3H), 1.51(t,  Mono-phenyl) -amide 3.12 (m, 4H), 2.65 (s, 3H), 1.51 (t,
J=7.5Hz, 3H)  J = 7.5Hz, 3H)
실시예 II： [2-메틸 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4- -카바민산에틸 에스터의 제조 Example II Preparation of [2-Methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazole-4--carbamate ethyl ester
단계 1: (2-메틸 -6-니트로—1H-벤즈이미다졸 -4-일) -카바민산 에틸에스터 상기 단계 1-2의 B에서 제조한 2-메틸 -6-니트로 -1H-벤즈이미다졸 -4- 카르복실산 (100 mg, 0.45 隱 ol)을 THF (4 mL)에 용해시킨 후 Et3N (0.19 mL, 1.35 誦 ol)과 다이페닐포스포릴아지드 (DPPAX0.194 mL, 0.90 隱 ol)를 적가하였다. 반웅 흔합물을 질소하에서 3시간 동안 환류 교반한 후 에탄올 (0.13 mL, 2.23 mmol)을 적가한 후 10시간 동안 환류 교반하였다. 상온으로 넁각 후 반응 흔합물을 감압 농축하였다. 남은 물질을 실리카와 다이클로로메탄 (DCM)/Me0H 100:1 전개액을 사용한 칼럼 크로마토그래피법을 이용， 정제하여 2-메틸ᅳ 6-니트로 -1H- 벤즈이미다졸 -4-일) -카바민산 에틸에스터 (49 mg, 41%)를 노란색 고체로 얻었다. Step 1: (2-Methyl-6-nitro-lH-benzimidazol-4-yl) -carbamic acid ethyl ester 2-methyl-6-nitro-lH-benzimidazole prepared in B of step 1-2 above -4- Carboxylic acid (100 mg, 0.45 μl ol) was dissolved in THF (4 mL), followed by Et 3 N (0.19 mL, 1.35 μl ol) and diphenylphosphoryl azide (DPPAX0.194 mL, 0.90 μl ol). Added dropwise. The reaction mixture was stirred under reflux for 3 hours under nitrogen, followed by dropwise addition of ethanol (0.13 mL, 2.23 mmol), followed by stirring under reflux for 10 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The remaining material was purified by column chromatography using silica and dichloromethane (DCM) / Me0H 100: 1 developer to afford 2-methyl ᅳ 6-nitro-1H-benzimidazol-4-yl) -carbamic acid. Ethyl ester (49 mg, 41%) was obtained as a yellow solid.
]H-NMR (400 MHz, DMS0_dG) δ： 8.43 (s, 1H), 8.10 (s, 1H), 5.76 (s, 1H), 4.21 (q, J = 7.2 Hz, 1H),2.59 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z: 265 [M+l]+ 단계 2: (6—아미노 -2-메틸 -1H—벤즈이미다졸 -4-일) -카바민산 에틸 에스터 상기 단계 1에서 제조한 2-메틸 -6-니트로 -1H-벤즈이미다졸 -4ᅳ일) -카바민산 에틸에스터 (66 mg, 0.25 圆 ol)를 에탄올 (3 mL)에 녹인 후 Raney-Ni (6.0 mg)을 첨가한다. 이 흔합물을 상은 및 수소하에서 10시간동안 교반한다. 반응촉매를 셀라이트를 이용해 여과하고 여액을 감압 농축 후， 실리카와 DCM/MeOH 50~30：1 전개액을 사용한 칼럼 크로마토그래피법을 이용하여 정제하여 (6-아미노 -2-메틸- 1H-벤즈이미다졸 -4-일) -카바민산 에틸 에스터 (34 g, 58%)를 흰색 고체로 얻었다. ] H-NMR (400 MHz, DMS0_d G ) δ: 8.43 (s, 1H), 8.10 (s, 1H), 5.76 (s, 1H), 4.21 (q, J = 7.2 Hz, 1H), 2.59 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H). MS (ESI +) m / z: 265 [M + l] + Step 2: (6—Amino-2-methyl-1H—benzimidazol-4-yl) -carbamic acid ethyl ester 2- Methyl-6-nitro-lH-benzimidazol-4xyl) -carbamic acid ethyl ester (66 mg, 0.25 x ol) is dissolved in ethanol (3 mL) and then Raney-Ni (6.0 mg) is added. This mixture is stirred for 10 hours under silver and hydrogen. The reaction catalyst was filtered through celite, the filtrate was concentrated under reduced pressure, purified by column chromatography using silica and DCM / MeOH 50-30: 1 developing solution (6-amino-2-methyl-1H-benz). Imidazol-4-yl) -carbamic acid ethyl ester (34 g, 58%) as a white solid.
-匪 R (400 MHz, DMS0-d6) δ： 11.6 (s, broad, 1H), 8.44 (s, broad, 1H), 6.86 (s, 1H), 6.29 (s, 1H), 4.80 (s, broad, 2H), 4.12 (q, J = 7.2 Hz, 2H), 2.37 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H) . MS (ESI+) m/z: 235 [M+l]+ 단계 3: [2—메틸 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H_벤즈이미다졸—4—일] - 카바민산 에틸 에스터
Figure imgf000075_0001
匪 R (400 MHz, DMS0-d 6 ) δ: 11.6 (s, broad, 1H), 8.44 (s, broad, 1H), 6.86 (s, 1H), 6.29 (s, 1H), 4.80 (s, broad, 2H), 4.12 (q, J = 7.2 Hz, 2H), 2.37 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H). MS (ESI &lt; + &gt;) m / z: 235 [M + l] + Step 3: [2—Methyl-6- (8-methyl-quinazolin-2-ylamino) -1 H_benzimidazole—4—yl]- Carbamic Acid Ethyl Ester
Figure imgf000075_0001
상기 단계 2에서 제조한 (6-아미노 -2-메틸 -1H-벤즈이미다졸 -4-일 )—카바민산 에틸 에스터 (1.3 g, 5.5瞧 ol)에 2-클로로 -8-메틸 퀴나졸린 (1.0 g, 5.6隱 ol)을 n- 부탄올 (39 ml)에 섞어 첨가한 후 130°C에서 14시간 동안 교반하였다. 상온으로 넁각 후 EtOAc (15 mL)로 회석한 후 10분동안 교반하였다. 고체 생성물을 여과 하여 얻은 후 EtOAc (5 ml)와 에테르 (10 ml)로 세척하여 회색 고체로 [2-메틸 -6- (8-메틸-퀴나졸린 -2-일아미 ί )-1Η—벤즈이미다졸—4-일] -카바민산 에틸 에스터 (1.9g, 92.3%)를 얻었다. To (6-amino-2-methyl-1H-benzimidazol-4-yl) -carbamic acid ethyl ester (1.3 g, 5.5 μL ol) prepared in step 2 above, 2-chloro-8-methyl quinazoline (1.0 g, 5.6 Pa ol) was added to n-butanol (39 ml), and the mixture was stirred at 130 ° C. for 14 hours. After cooling to room temperature, it was distilled with EtOAc (15 mL) and stirred for 10 minutes. The solid product was obtained by filtration, washed with EtOAc (5 ml) and ether (10 ml) to obtain [2-methyl-6- (8-methyl-quinazolin-2-ylami ί) -1Η—benzimi as a gray solid. Dazol-4-yl] -carbamic acid ethyl ester (1.9 g, 92.3%) was obtained.
匪 R (DMSO-ds, ppm): δ 1.27 (t, 3H), 2.68 (s, 3H), 2.76 (s, 3H), 4.19 匪 R (DMSO-ds, ppm): δ 1.27 (t, 3H), 2.68 (s, 3H), 2.76 (s, 3H), 4.19
(q, 2H), 7.32 (t, 1H), 7.71-7.79 (m, 2H), 7.85 (s, 1H) ' 8.66 (s, 1H), 9.30 (s, 1H), 9.80 (s, 1H), 10.26 (s, 1H). 실시예 II를 웅용하여 각각 상응하는 출발물질을 이용하여 하기 표 3에 기재된 실시예의 화합물을 제조하였다. (q, 2H), 7.32 (t, 1H), 7.71-7.79 (m, 2H), 7.85 (s, 1H) ' 8.66 (s, 1H), 9.30 (s, 1H), 9.80 (s, 1H), 10.26 (s, 1 H). Example II was used to prepare the compounds of the examples set forth in Table 3 below, respectively using the corresponding starting materials.
[표 3] TABLE 3
Figure imgf000076_0001
에스터 3H), 2.67(s, 3H), 2.21(m, 1H),
Figure imgf000076_0001
Ester 3H), 2.67 (s, 3H), 2.21 (m, 1H),
1.10(m, 7H)  1.10 (m, 7H)
실시예 III: 2-메틸 -^-(8-메틸-퀴나졸린 -2-일 )-1Η-벤즈이미다졸 -4， 6- 다이아민의 제조 Example III Preparation of 2-methyl-^-(8-methyl-quinazolin-2-yl) -1Η-benzimidazole-4, 6-diamine
Figure imgf000077_0001
Figure imgf000077_0001
상기 단계 II에서 제조한 [2—메틸— 6-(8-메틸 -퀴나졸린— 2-일아미노)— 1H- 벤즈이미다졸 -4-일]—카바민산 에틸 에스터 (0.31 g, 0.82 誦 ol)를 에탄올 (3.30 ml)과 3N NaOH (1.20 ml)의 혼합물에 녹인 후 1200C에서 7시간 동안 환류 교반 후 용매양을 감압 농축하여 2/3로 줄였다. 물 (5.00 ml)을 추가하고 EtOAc (20 mL * 3)로 추출하였다. 모아진 유기층을 무수 MgS04로 건조시키고 감압 농축하여 노란색 고체 상태로 2-메틸 -N6-(8-메틸-퀴나졸린 -2-일) -1H-벤즈이미다졸 -4，6-다이아민 (0.19 g, 77.6%)을 얻었다. [2—Methyl-6- (8-methyl-quinazolin—2-ylamino) —1H-benzimidazol-4-yl] —carbamic acid ethyl ester (0.31 g, 0.82 誦 ol) prepared in step II above. Was dissolved in a mixture of ethanol (3.30 ml) and 3N NaOH (1.20 ml), and the mixture was stirred under reflux at 120 0 C for 7 hours, and the solvent was concentrated under reduced pressure to reduce to 2/3. Water (5.00 ml) was added and extracted with EtOAc (20 mL * 3). The combined organic layers were dried over anhydrous MgSO 4 and concentrated under reduced pressure to yield 2-methyl-N 6- (8-methyl-quinazolin-2-yl) -1H-benzimidazole-4,6-diamine (0.19) as a yellow solid. g, 77.6%).
카르복실산 (DMS0-d6) ppm): δ 2.41 (s, 3H), 2.63 (s, 3H), 4.98 (s, 2H), 6.69 (s, 1H), 7.21 (t, 1H), 7.62-7.69 (m,2H), 7.80 (s,lH),9.16 (s,lH), 9.50 (s,lH).11.75 (s,lH). 상기 실시예 111의 반응을 응용하여 각각 상응하는 출발물질을 이용하여 하기 표 4에 기재된 실시예의 화합물을 제조하였다. [표 4] Carboxylic Acid (DMS0-d 6) ppm): δ 2.41 (s, 3H), 2.63 (s, 3H), 4.98 (s, 2H), 6.69 (s, 1H), 7.21 (t, 1H), 7.62- 7.69 (m, 2H), 7.80 (s, lH), 9.16 (s, lH), 9.50 (s, lH). 11.75 (s, lH). The reaction of Example 111 was applied to prepare the compounds of the examples set forth in Table 4 below using the corresponding starting materials, respectively. TABLE 4
화합물명 ¾ N R  Compound Name ¾ N R
]H NMR (300 MHz, DMS0_d6) 9.65 (s, 1H), 9.22 (s, 1H), 8.16 ] H NMR (300 MHz, DMS0_d 6 ) 9.65 (s, 1H), 9.22 (s, 1H), 8.16
NG- (7-브로모-퀴나졸린 -2- (brs, 1H), 7.80 (d, J=8.7 Hz, 일) -2ᅳ메틸 -1H- 1H), 7.75 (s, 1H), 7.44 (dd, 벤즈이미다졸 -4,6- J=8.7, 2.1 Hz, 1H), 7.39 (s, 다이아민 N G- (7-bromo-quinazolin-2- (brs, 1H), 7.80 (d, J = 8.7 Hz, day) -2 ᅳ methyl-1H-1H), 7.75 (s, 1H), 7.44 ( dd, benzimidazole-4,6-J = 8.7, 2.1 Hz, 1H), 7.39 (s, diamine
1H), 6.87 (s, 1H), 5.08 (brs, 2H), 2.40 (s, 3H)  1H), 6.87 (s, 1H), 5.08 (brs, 2H), 2.40 (s, 3H)
2-사이클로프로필- N6-(8- ¾ NMR (300 MHz, DMS0-d6, δ ) ： 메틸-퀴나졸린 -2-일) -1H- 11.75(s, 1H), 9.53(s, 1H), 벤즈이미다졸ᅳ 4,6- 9.19(s, 1H), 7.78(s, 1H), 다이아민 7.72(m, 2H), 7.27(t, 1H) , 2-cyclopropyl-N 6- (8-¾ NMR (300 MHz, DMS0-d 6 , δ): methyl-quinazolin-2-yl) -1H-11.75 (s, 1H), 9.53 (s, 1H) , Benzimidazole ᅳ 4,6- 9.19 (s, 1H), 7.78 (s, 1H), diamine 7.72 (m, 2H), 7.27 (t, 1H),
6.71(s, 1H), 4.95(s, 1H) , 2.63(s, 3H), 2.46(m, 1H), 1.12(m, 4H)  6.71 (s, 1H), 4.95 (s, 1H), 2.63 (s, 3H), 2.46 (m, 1H), 1.12 (m, 4H)
¾應 R (300 MHz, DMSO-de) 11.60 (s, 1H), 9.44 (s, 1H), 9.16 (s, ¾ 應 R (300 MHz, DMSO-de) 11.60 (s, 1H), 9.44 (s, 1H), 9.16 (s,
NG-(8-이소프로폭시- 1H), 7.59 (s, 1H), 7.46 (d, 퀴나졸린— 2-일) -2-메틸- J=8.1 Hz, 1H), 7.23 (m, 2H), 1H-벤즈이미다졸 -4,6- 6.70 (s, 1H), 4.90 (brs, 2H), 다이아민 N G- (8-isopropoxy-1H), 7.59 (s, 1H), 7.46 (d, quinazolin- 2-yl) -2-methyl-J = 8.1 Hz, 1H), 7.23 (m, 2H) , 1H-benzimidazole -4,6- 6.70 (s, 1H), 4.90 (brs, 2H), diamine
4.86 (in, 1H), 2.41 (s, 3H)， 1.36 (dd, J=5.7, 1.8 Hz, 6H) NMR (300 MHz, DMS0-d6) 11.80 4.86 (in, 1H), 2.41 (s, 3H), 1.36 (dd, J = 5.7, 1.8 Hz, 6H) NMR (300 MHz, DMS0-d 6 ) 11.80
(s, 1H), 9.82 (s, 1H), 9.26 (s,  (s, 1H), 9.82 (s, 1H), 9.26 (s,
N6-(8-클로로-퀴나졸린 -2- 1H), 8.02 (s, 1H), 7.94 (dd, N 6- (8-chloro-quinazolin-2-1H), 8.02 (s, 1H), 7.94 (dd,
일) -2-메틸 -1H- J=7.2, 1.2 Hz, 1H), 7.55 (dd,  Il) -2-methyl-1H-J = 7.2, 1.2 Hz, 1H), 7.55 (dd,
53 325.3 벤즈이미다졸ᅳ 4,6- J=8.1, 1.2 Hz, 1H), 7.29 (t,  53 325.3 Benzimidazolazole 4,6-J = 8.1, 1.2 Hz, 1H), 7.29 (t,
다이아민 J=8.1 Hz, 1H), 6.66 (d, J=1.8  Diamine J = 8.1 Hz, 1H), 6.66 (d, J = 1.8)
Hz, 1H), 4.98 (s, 2H), 2.41 (d,  Hz, 1H), 4.98 (s, 2H), 2.41 (d,
J=6.0 Hz, 3H)  J = 6.0 Hz, 3H)
실시예 IV: 2-다이메틸아미노 -N-[2-메틸 -6-(8-메틸-퀴나졸린 -2-일아미노) - 1H-벤즈이미다졸 -4-일] -아세트아미드의 제조 Example IV Preparation of 2-dimethylamino-N- [2-methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -acetamide
Figure imgf000079_0001
Figure imgf000079_0001
상기 실시예 III에서 제조한 2—메틸 -N6ᅳ (8-메틸-퀴나졸린 -2—일) -1H- 벤즈이미다졸 -4 ,6-다이아민 (O.lg, 0.31 圆 ole)을 THF 3 ml에 용해시킨 후 Et3N (0.12 ml)와 Ν,Ν-다이메틸아미노-아세틸 클로라이드 (200 mg, 0.94 mmole)를 상은에서 적가한 후 10CTC에서 10시간 동안 환류 교반하였다. 상은으로 넁각 후 물 (10 ml)을 첨가하고 EtOAc (20ml * 3)로 추출한다. 유기층을 무수 Na2S04로 건조후 감압 농축한다ᅳ 50:1의 MC ： MeOH와 실리카를 이용한 칼럼 크로마토그래피법으로 정제하여 열은 노란색 고체상태의 실시예 1의 2-다이메틸아미노 -N-[2-메틸 -6— (8- 메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸ᅳ 4—일] -아세트아미드를 (72 mg) 60% 수율로 얻었다. 2—Methyl-N 6 ' (8-methyl-quinazolin-2-yl) -1H-benzimidazole-4,6-diamine (O.lg, 0.31 圆 ole) prepared in Example III above was THF After dissolving in 3 ml, Et 3 N (0.12 ml) and Ν, Ν-dimethylamino-acetyl chloride (200 mg, 0.94 mmole) were added dropwise in phase silver, followed by stirring under reflux for 10 hours at 10 CTC. After quenching with phase silver, water (10 ml) is added and extracted with EtOAc (20ml * 3). The organic layer was dried over anhydrous Na 2 S0 4, and concentrated under reduced pressure. 50: 1 MC: Purified by column chromatography using MeOH and silica, and the residue was heated to 2-dimethylamino-N- as a yellow solid. [2-Methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazolyl 4-yl] -acetamide (72 mg) was obtained in 60% yield.
]H NMR (300 MHz, DMS0, δ): 9.82 (s, 1H), 9.75(s, 1H), 9.23(s, 1H), ] H NMR (300 MHz, DMS0, δ): 9.82 (s, 1H), 9.75 (s, 1H), 9.23 (s, 1H),
8.40(br s, 1H), 8.24(s, 1H), 8.16(br s, 1H), 7.73(d, J=8.4Hz, 1H), 7.68(d, J=6.6Hz, 1H), 7.26(t, 1=7.2 Hz, 1H), 3.15(s, 3H), 2.67(s, 3H), 2.57(s, 2H), 2.36(s, 3H), 2.47(s, 3H) 상기 실시예 IV의 제조방법을 응용하여 각각 상응하는 출발물질을 이용하여 하기 표 5에 기재된 실시예의 화합물을 제조하였다. 8.40 (br s, 1H), 8.24 (s, 1H), 8.16 (br s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 6.6 Hz, 1H), 7.26 (t, 1 = 7.2 Hz, 1H), 3.15 (s, 3H), 2.67 (s, 3H), 2.57 (s, 2H), 2.36 (s, 3H), 2.47 ( s, 3H) The compounds of the examples described in Table 5 below were prepared using the corresponding starting materials by applying the preparation method of Example IV.
[표 5] TABLE 5
Figure imgf000080_0001
일] -아미드 1H), 3.62-3.65(m, 4H), 3.44-3.47(m,
Figure imgf000080_0001
General] -amide 1H), 3.62-3.65 (m, 4H), 3.44-3.47 (m,
4H), 2.64(s, 3H), 2.47(s, 3H)  4H), 2.64 (s, 3H), 2.47 (s, 3H)
4-메틸-피페라진 -1- ¾ NMR (300 MHz, DMS0-d6> δ ) ： 4-Methyl-piperazine-1- ¾ NMR (300 MHz, DMS0-d 6> δ):
카르복실산 [2-메틸 -6- 9.72(s, IH), 9.20(s, IH), 8.15- (8-메틸-퀴나졸린 -2- 8.21(m, 3H), 7.79(br s, IH), 7.64-Carboxylic Acid [2-Methyl-6-9.72 (s, IH), 9.20 (s, IH), 8.15- (8-Methyl-Quinazoline-2- 8.21 (m, 3H), 7.79 (br s, IH) , 7.64-
431.1 일아미노) -1H- 7.71(m, 2H), 7.23(t, J=7.2 Hz, IH), 431.1 monoamino) -1H-7.71 (m, 2H), 7.23 (t, J = 7.2 Hz, IH),
벤즈이미다졸 -4-일] - 3.47(br s, 4H) , 2.64(s, 3H), 2.46(s, 아미드 3H), 2.37(br s, 4H), 2.22(s, 3H) Benzimidazol-4-yl] -3.47 (br s, 4H), 2.64 (s, 3H), 2.46 (s, amide 3H), 2.37 (br s, 4H), 2.22 (s, 3H)
¾ NMR (300 MHz, DMSO, δ ) ：  ¾ NMR (300 MHz, DMSO, δ) ：
N-[2-메틸— 6-(8-메틸- 10.75(s( IH), 9.76(s, IH), 9.20(s, N- [2-methyl- 6- (8-methyl-10.75 (s ( ih)), 9.76 (s, ih), 9.20 (s,
퀴나졸린— 2-일아미노) - IH), 8.22(m, 2H), 8.15(s, IH), 7.71- 1H-벤즈이미다졸 -4- 444.1 Quinazolin- 2-ylamino) -IH), 8.22 (m, 2H), 8.15 (s, IH), 7.71-1H-benzimidazole-4-444.1
7.64(iii, 2H), 7.23(t, J=7.5Hz, IH),  7.64 (iii, 2H), 7.23 (t, J = 7.5 Hz, IH),
일] -3-피페리딘 -1—일- 2.71(s, 3H), 2.55(m, 4H), 2.46(s, General] -3-piperidine-1-yl- 2.71 (s, 3H), 2.55 (m, 4H), 2.46 (s,
프로피온아미드 Propionamide
3H), 1.72(iii, 4H), 1.55— 1.32(m, 6H)  3H), 1.72 (iii, 4H), 1.55— 1.32 (m, 6H)
¾ NMR (300 MHz, DMS0-d6, δ ) ： ¾ NMR (300 MHz, DMS0-d 6 , δ) ：
1-[2—메틸 -6-(8—메틸- 9.63(s, IH), 9.19(s, IH), 8.52(s,  1- [2—methyl-6- (8—methyl-9.63 (s, IH), 9.19 (s, IH), 8.52 (s,
퀴나졸린 -2-일아미노) - IH), 8.09-8.15(m, 3H), 7.63-7.70(m, Quinazolin-2-ylamino) -IH), 8.09-8.15 (m, 3H), 7.63-7.70 (m,
1H-벤즈이미다졸 -4- 2H), 7.22(t, J=7.5 Hzᅳ IH), 6.94(s, 461.5 일] -3-(2-모폴린 -4-일- IH), 3.57-3.60(m, 4H)ᅳ 3.20-3.26(m, 1H-benzimidazole-4-2H), 7.22 (t, J = 7.5 Hz ᅳ IH), 6.94 (s, 461.5 days) -3- (2-morpholin-4-yl-IH), 3.57-3.60 ( m, 4H) ᅳ 3.20-3.26 (m,
에틸) -우레아 2H), 2.64(s, 3H), 2.46(s, 3H), 2.37- 2.39(m, 6H) Ethyl) -urea 2H), 2.64 (s, 3H), 2.46 (s, 3H), 2.37-2.39 (m, 6H)
1-(3-다이메틸아미노- ¾ NMR (300 MHz, DMS0_d6, δ ) ： 1- (3-dimethylamino-¾NMR (300 MHz, DMS0_d 6 , δ):
프로필 )-3-[2-메틸 -6- 9.61(s, IH), 9.18(s, IH)ᅳ 8.43(s, Propyl) -3- [2-methyl-6- 9.61 (s, IH), 9.18 (s, IH) ᅳ 8.43 (s,
(8-메틸-퀴나졸린 -2- IH), 8.20(br s, IH), 8.09(m, 2H), 433.3 일아미노) -1H- 그 62-7.70(ITI, 2H), 7.22(t, J=7.8 Hz, (8-methyl-quinazolin-2-IH), 8.20 (br s, IH), 8.09 (m, 2H), 433.3 monoamino) -1H- 62-2.70 (ITI, 2H), 7.22 (t, J = 7.8 Hz,
벤즈이미다졸 -4-일] - IH), 6.98(s, IH), 3.12-3.15 (m, 4H), 우레아 2.64(s, 3H), 2.46(s, 3H), 2.30(s, Benzimidazol-4-yl] -IH), 6.98 (s, IH), 3.12-3.15 (m, 4H), Urea 2.64 (s, 3H), 2.46 (s, 3H), 2.30 (s,
6H), 2.62-2.65(m, 2H)  6H), 2.62-2.65 (m, 2H)
N-[2-메틸 -6-(8-메틸- ]H NMR (300 MHz, DMS0-ds) 9.73 (s, N- [2-methyl-6- (8-methyl- ] H NMR (300 MHz, DMS0-d s ) 9.73 (s,
퀴나졸린 -2-일아미노) - IH), 9.45 (brs, IH), 9.20 (s, IH), Quinazolin-2-ylamino) -IH), 9.45 (brs, IH), 9.20 (s, IH),
1H-벤즈이미다졸 -4- 8.25 (brs, IH), 8.20 (s, IH)， 7.67 1H-benzimidazole-4-8.25 (brs, IH), 8.20 (s, IH), 7.67
473.4 일] -4- (4—메틸- (dd, J=15.6, 8.1 Hz, 2H), 7.23 (t,  473.4yl] -4- (4—methyl- (dd, J = 15.6, 8.1 Hz, 2H), 7.23 (t,
피페라진 -1—일) - J=7.2 Hz, IH), 2.63 (s, 3H), 2.42 (m, 부틸아미드 15H), 2.11 (s, 3H), 1.74 (m, 2H) Piperazine-1-yl)-J = 7.2 Hz, IH), 2.63 (s, 3H), 2.42 (m, butylamide 15H), 2.11 (s, 3H), 1.74 (m, 2H)
[6-(7-브로모- ]H NMR (300 MHz, DMS0-ds) 10.34 (s, [6- (7-Bromo- ] H NMR (300 MHz, DMS0-d s ) 10.34 (s,
퀴나졸린ᅳ 2-일아미노) - IH), 9.86 (brs, IH), 9.38 (s, IH), Quinazolinyl 2-ylamino)-IH), 9.86 (brs, IH), 9.38 (s, IH),
2-메틸 -1H- 8.32 (s, IH), 8.08 (s, IH), 7.91 (m, 442 벤즈이미다졸 -4-일] - 2H), 7.59 (d, J=7.8 Hz, IH), 4.24 (m, 카바민산에틸 에스터 2H), 2.84 (s, 3H), 1.37(m, 3H)  2-methyl-1H- 8.32 (s, IH), 8.08 (s, IH), 7.91 (m, 442 benzimidazol-4-yl]-2H), 7.59 (d, J = 7.8 Hz, IH), 4.24 (m, ethyl carbamate 2H), 2.84 (s, 3H), 1.37 (m, 3H)
]H NMR (300 MHz, DMS으 d6) ： ] H NMR (300 MHz, d 6 with DMS) ：
1-[2—메틸 -6-(8-메틸- 9.62(s, IH), 9.19(s, IH), 8.54(s,  1- [2—Methyl-6- (8-methyl-9.62 (s, IH), 9.19 (s, IH), 8.54 (s,
퀴나졸린 -2-일아미노) - IH), 8.20(br s, IH), 8.09(s, 2H), Quinazolin-2-ylamino)-IH), 8.20 (br s, IH), 8.09 (s, 2H),
1H-벤즈이미다졸 -4- 7.63-7.70(m, 2H), 7.22(t, J=7.5 Hz, 459.2 일] -3-(2-피페리딘 -1- IH), 6.93(br s, IH), 3.22-3.23(m, 1H-benzimidazole-4- 7.63-7.70 (m, 2H), 7.22 (t, J = 7.5 Hz, 459.2 day) -3- (2-piperidine-1-IH), 6.93 (br s, IH ), 3.22-3.23 (m,
일-에틸) -우레아 2H), 2.64(s, 3H), 2.39-2.42(m, 5H), Yl-ethyl) -urea 2H), 2.64 (s, 3H), 2.39-2.42 (m, 5H),
1.52-1.62(m, 8H), 1.38-1.42(m, 2H)  1.52-1.62 (m, 8H), 1.38-1.42 (m, 2H)
¾ NMR (300 MHz, DMS0-d6( δ ) ： ¾ NMR (300 MHz, DMS0-d 6 ( δ) ：
피페리딘 -1-카르복실산 Piperidine-1-carboxylic acid
9.70(s, IH), 9.20(s, IH), 8.19(s,  9.70 (s, IH), 9.20 (s, IH), 8.19 (s,
[2-메틸ᅳ 6-(8-메틸- IH), 8.09-8.12(m, 2H), 7.82(br s, [2-Methyl ᅳ 6- (8-methyl-IH), 8.09-8.12 (m, 2H), 7.82 (br s,
퀴나졸린 -2-일아미노) - 416.1 Quinazolin-2-ylamino)-416.1
IH), 7.64-7.71 (m, 2H), 7.22(t, J=7.5  IH), 7.64-7.71 (m, 2H), 7.22 (t, J = 7.5)
1H-벤즈이미다졸 -4- Hz, IH), 3. 5-3.47 (m, 4H), 2.64(s, 1H-benzimidazole-4-Hz, IH), 3.5-3.47 (m, 4H), 2.64 (s,
일] -아미드 General] -amide
3H), 2.45(s, 3H), 1.54-1.56(m, 6H) l-(3-다이메틸아미노- ¾ NMR (300 MHz, CD30D, δ ) ： 3H), 2.45 (s, 3H), 1.54-1.56 (m, 6H) l- (3-dimethylamino-¾ NMR (300 MHz, CD 3 0D, δ):
프로필 )-1-메틸 -3-[2- 9.09(s, IH), 8.42(s, IH), 7.64- 메틸 -6- (8-메틸- 7.66(m, 3H), 7.24(t, J=7.5 Hz, IH), Propyl) -1-methyl-3- [2- 9.09 (s, IH), 8.42 (s, IH), 7.64-methyl-6- (8-methyl-7.66 (m, 3H), 7.24 (t, J = 7.5 Hz, IH),
447.1 퀴나졸린 -2-일아미노) - 3.54(t, J=6.6 Hz, 2H) 3.16(s, 3H),  447.1 Quinazolin-2-ylamino)-3.54 (t, J = 6.6 Hz, 2H) 3.16 (s, 3H),
1H-벤즈이미다졸 -4- 2.81(t, J=6.9 Hz, 2H) 2.72(s, 3H), 1H-benzimidazole-4-2.81 (t, J = 6.9 Hz, 2H) 2.72 (s, 3H),
일] -우레아 2.57(111， 9H), 1.96(t, J=6.9 Hz, 2H) General] -urea 2.57 (111 ， 9H), 1.96 (t, J = 6.9 Hz, 2H)
4-메틸-피페라진 -1- ¾ NMR (300 MHz, DMS으 d6, δ ) ： 4-Methyl-piperazine-1- ¾ NMR (300 MHz, d 6 in DMS, δ):
카르복실산 [6-(8- 9.77(s, IH); 9.22(s, IH), 8.23(s, Carboxylic acids [6- (8-9.77 (s, IH); 9.22 (s, IH), 8.23 (s,
메틸—퀴나졸린 -2- IH), 8.13(s, IH), 8.01(s, IH), 7.65-Methyl—quinazolin-2-IH), 8.13 (s, IH), 8.01 (s, IH), 7.65-
417 일아미노) -1H- 7.73(iii, 2H), 7.25(t, J=7.5 Hz, IH), 417 monoamino) -1H-7.73 (iii, 2H), 7.25 (t, J = 7.5 Hz, IH),
벤즈이미다졸 -4-일] - 6.85(s, IH), 3.53(m, 4H), 2.62(s, Benzimidazol-4-yl] -6.85 (s, IH), 3.53 (m, 4H), 2.62 (s,
아미드 3H), 2.37(m, 4H) , 2.18(s, 3H) Amide 3H), 2.37 (m, 4H), 2.18 (s, 3H)
피페리딘 -1-카르복실산 ¾ NMR (300 MHz, CD30D, δ ) ： Piperidine-1-carboxylic acid ¾ NMR (300 MHz, CD 3 0D, δ) ：
[6ᅳ(8-메틸-퀴나졸린- 9.09(s, IH), 8.15-8.18(m, 2H), 7.63- 2-일아미노) -1H- 7.66(m, 2H), 7.25(t, J=7.8 Hz, IH) , 402.5 벤즈이미다졸 -4-일 ] - 6.87(s, IH), 3.55-3.61(m, 4H), [6 ′ (8-Methyl-quinazolin-9.09 (s, IH), 8.15-8.18 (m, 2H), 7.63-2-ylamino) -1H-7.66 (m, 2H), 7.25 (t, J = 7.8 Hz, IH), 402.5 benzimidazol-4-yl] -6.87 (s, IH), 3.55-3.61 (m, 4H),
아미드 2.70(s, 3H), 1.65-1.78(m, 6H) Amide 2.70 (s, 3H), 1.65-1.78 (m, 6H)
Ή NMR (300 MHz, DMS0-d6l δ ) ： Ή NMR (300 MHz, DMS0- d 6l δ):
1-(3ᅳ다이메틸아미노- 9.61(s, IH), 9.18(s, IH)， 8.56(s,  1- (3 ᅳ dimethylamino-9.61 (s, IH), 9.18 (s, IH), 8.56 (s,
2， 2—다이메틸―프로필) - IH), 8.12-8.16(m, 2H), 8.06(s, IH), 2, 2—dimethyl-propyl) -IH), 8.12-8.16 (m, 2H), 8.06 (s, IH),
3-[2-메틸ᅳ6-(8-메틸- 7.62-7.70(111， 2H), 7.22(t, J=7.5 Hz, 461.1 퀴나졸린 -2-일아미노) - IH), 6.86(br s, IH), 2.98-3.00 (m, 3- [2-Methyl ᅳ 6- (8-methyl-7.62-7.70 (111, 2H), 7.22 (t, J = 7.5 Hz, 461.1 quinazolin-2-ylamino) -IH), 6.86 (br s, IH), 2.98-3.00 (m,
1H-벤즈이미다졸 -4ᅳ 1H-benzimidazole-4
2H), 2.63(s, 3H), 2.46(s, 3H),  2H), 2.63 (s, 3H), 2.46 (s, 3H),
일] -우레아 Day] -urea
2.25(s, 6H), 2.12(s, 2H)， 0.84(s, 6H) .¾ NMR (300 MHz, DMSO— d6, δ ) ： 2.25 (s, 6H), 2.12 (s, 2H), 0.84 (s, 6H) .¾ NMR (300 MHz, DMSO— d 6 , δ) ：
l-[2-메틸 -6-(8-메틸- 9.61(s, IH), 9.18(s, IH), 8.41(s, l- [2-methyl-6- (8-methyl-9.61 (s, IH), 9.18 (s, IH), 8.41 (s,
퀴나졸린 -2-일아미노) - IH), 8.20(br s, IH), 8.09(m, 2H), Quinazolin-2-ylamino) -IH), 8.20 (br s, IH), 8.09 (m, 2H),
1H-벤즈이미다졸 -4- 7.62-7.70(m, 2H), 7.22(t, J=7.5 Hz, 459.3 일] -3-(3-피를리딘 -1- IH), 6.98(s, IH), 3.15(ni, 4H), 2.63- 일-프로필) -우레아 2.68(m, 7H), 2.46(s, 3H), 1.65- 1.74(m, 6H)  1H-benzimidazole-4- 7.62-7.70 (m, 2H), 7.22 (t, J = 7.5 Hz, 459.3 days) -3- (3-pyridine-1-IH), 6.98 (s, IH) , 3.15 (ni, 4H), 2.63- yl-propyl) -urea 2.68 (m, 7H), 2.46 (s, 3H), 1.65- 1.74 (m, 6H)
]H NMR (300 MHz, DMSO— ds, δ ) ： ] H NMR (300 MHz, DMSO— d s , δ) ：
9.69(s, IH), 9.20(s, IH), 8.57(s,  9.69 (s, IH), 9.20 (s, IH), 8.57 (s,
1- (3-다이메틸아미노- IH), 8.27(br s, IH), 8.16-8.18(m,  1- (3-dimethylamino-IH), 8.27 (br s, IH), 8.16-8.18 (m,
프로필 )-3-[6— (8-메틸- 2H), 8.02(s, IH), 그 63-7.71(m, 2H), 퀴나졸린 -2-일아미노) - 419.1 Propyl) -3- [6— (8-methyl-2H), 8.02 (s, IH), 63-7.71 (m, 2H), quinazolin-2-ylamino)-419.1
7.23(t, J=7.5 Hz, IH), 7.02(s, IH),  7.23 (t, J = 7.5 Hz, IH), 7.02 (s, IH),
1H-벤즈이미다졸 -4- 3.12-3.16(m, 2H), 2.64(s, 3H), 1H-benzimidazole-4- 3.12-3.16 (m, 2H), 2.64 (s, 3H),
일] -우레아 Day] -urea
2.35(t, J=7.2 Hz, 2H), 2.20(s, 6H),  2.35 (t, J = 7.2 Hz, 2H), 2.20 (s, 6H),
1.57-1.62(m, 2H)  1.57-1.62 (m, 2H)
¾ NMR (300 MHz, DMSOd (；， δ ) ：  ¾ NMR (300 MHz, DMSOd (; δ) ：
1- (3-다이메틸아미노- 9.56(s, IH), 9.17(s, IH), 8.44(s,  1- (3-dimethylamino-9.56 (s, IH), 9.17 (s, IH), 8.44 (s,
프로필 )-3-[6-(8- IH), 8.23(br s, IH), 7.93-7.97(m, Propyl) -3- [6- (8-IH), 8.23 (br s, IH), 7.93-7.97 (m,
이소프로폭시- 2H), 7.44(d, j=7.5 Hz, IH) , 7.19- 퀴나졸린 -2-일아미노) - 477.1 Isopropoxy-2H), 7.44 (d, j = 7.5 Hz, IH), 7.19-quinazolin-2-ylamino)-477.1
7.27(m, 2H), 6.99(s, IH), 4.85(quin. ,  7.27 (m, 2 H), 6.99 (s, IH), 4.85 (quin.,
2-메틸 -1H- j=6.0 Hz, IH), 3.12-3.15(m, 2H),  2-methyl-1H-j = 6.0 Hz, IH), 3.12-3.15 (m, 2H),
벤즈이미다졸 -4-일] - 2.52-2.54(m, 5H), 2.33(s, 6H), Benzimidazol-4-yl]-2.52-2.54 (m, 5H), 2.33 (s, 6H),
우레아 Urea
1.63(m, 2H), 1.33(d, j=5.4 1.63 (m, 2 H), 1.33 (d, j = 5.4)
Figure imgf000085_0001
Figure imgf000085_0001
f6lZ.00/ll0Za¾X3d ΟόΟΜ^Ο/ΖΪΟΖ OAV 일아미노) -1H- 3.45-3.48(m, 4H), 2.64(s, 3H), 2.34- 벤즈이미다졸 -4—일 ] - 2.38(m( 4H), 2.22(s, 3H), 2.12(quin. , 아미드 J=6.6 Hz, IH), 1.00-1.02(111， 4H) f6lZ.00 / ll0Za¾X3d ΟόΟΜ ^ Ο / ΖΪΟΖ OAV Monoamino) -1H-3.45-3.48 (m, 4H), 2.64 (s, 3H), 2.34-benzimidazole-4-yl] -2.38 (m ( 4H), 2.22 (s, 3H), 2.12 (quin) , Amide J = 6.6 Hz, IH), 1.00-1.02 (111, 4H).
¾丽 R (300 MHz, DMS0-d6, δ ) ： ¾ 丽 R (300 MHz, DMS0-d 6 , δ) ：
4-이소프로필- 9.71(s, IH), 9.20(s, IH), 8.13- 피페라진 -1-카르복실산  4-isopropyl-9.71 (s, IH), 9.20 (s, IH), 8.13- piperazine-1-carboxylic acid
8.21(m, 3H), 7.79(s, IH), 7.64- 8.21 (m, 3H), 7.79 (s, IH), 7.64-
[2-메틸ᅳ 6-(8—메틸- 7.71(m, 2H), 7.23(t, IH), 3.49(m, 459.1 퀴나졸린 -2-일아미노)ᅳ [2-Methyl ᅳ 6- (8—methyl-7.71 (m, 2H), 7.23 (t, IH), 3.49 (m, 459.1 quinazolin-2-ylamino) ᅳ
4H), 3.37(m, 4H), 2.64(s, 3H),  4H), 3.37 (m, 4H), 2.64 (s, 3H),
1H-벤즈이미다졸 -4- 2.55(m, 4H), 2.46(s, 3H), 1.02(d, 1H-benzimidazole-4- 2.55 (m, 4H), 2.46 (s, 3H), 1.02 (d,
일] -아미드 General] -amide
J=5.4 Hz, 6H)  J = 5.4 Hz, 6H)
¾ NMR (300 MHz, DMS0-d6, δ ) : ¾ NMR (300 MHz, DMS0-d 6 , δ):
모폴린 -4-카르복실산 Morpholine-4-carboxylic acid
9.70(s, IH), 9.19(s, IH), 8.20(br s,  9.70 (s, IH), 9.19 (s, IH), 8.20 (br s,
[2-사이클로프로필 -6— [2-cyclopropyl-6—
IH), 8.13-8.16(m, 2H), 7.80(s, IH) ,  IH), 8.13-8.16 (m, 2H), 7.80 (s, IH),
(8-메틸-퀴나졸린 -2- 7.63-7.71 (m, 2H), 7.22(t, J=7.5 Hz, 444.1 일아미노) -1H- IH), 3.62-3.65(ii), 4H), 3.44-3.47(m, (8-methyl-quinazolin-2- 7.63-7.71 (m, 2H), 7.22 (t, J = 7.5 Hz, 444.1 monoamino) -1H-IH), 3.62-3.65 (ii), 4H), 3.44- 3.47 (m,
벤즈이미다졸 -4-일] - 4H), 2.64(s, 3H), 2.12(quin. , J=6.9 Benzimidazol-4-yl] -4H), 2.64 (s, 3H), 2.12 (quin., J = 6.9
아미드 amides
Hz, IH), 1.00-1.02(m, 4H)  Hz, IH), 1.00-1.02 (m, 4H)
¾ NMR (300 MHz, DMS0-d6, δ ) ： ¾ NMR (300 MHz, DMS0-d 6 , δ) ：
모폴린 -4-카르복실산 9.65(s, IH), 9.19(s, IH), 8.25(s, Morpholine-4-carboxylic acid 9.65 (s, IH), 9.19 (s, IH), 8.25 (s,
[6-(8-이소프로폭시- IH), 8.14(s, IH), 8.02(s, IH),  [6- (8-isopropoxy-IH), 8.14 (s, IH), 8.02 (s, IH),
퀴나졸린 -2-일아미노) - 7.78(s, IH), 7.44(d, J=7.8 Hz, IH) , Quinazolin-2-ylamino) -7.78 (s, IH), 7.44 (d, J = 7.8 Hz, IH),
462.1 462.1
2-메틸ᅳ 1H- 7.18-7.28(m, 2H), 4.85(quin. , J=6.3 2-Methyl ᅳ 1H- 7.18-7.28 (m, 2H), 4.85 (quin., J = 6.3
벤즈이미다졸 -4-일] - Hz, IH), 3.61-3.64(III, 4H), 3.43- 아미드 3.47(m, 4H), 2.46(s, 3H), 1.35(d, Benzimidazol-4-yl] -Hz, IH), 3.61-3.64 (III, 4H), 3.43-amide 3.47 (m, 4H), 2.46 (s, 3H), 1.35 (d,
j=6.3 Hz, 6H) ¾匪 R (300 MHz, DMS0-d6, δ ) ： j = 6.3 Hz, 6H) ¾ 匪 R (300 MHz, DMS0-d 6 , δ) ：
4-이소프로필- 4-isopropyl-
9.65(s, IH), 9.19(s, IH), 8.13- 피페라진 -1—카르복실산 9.65 (s, IH), 9.19 (s, IH), 8.13- piperazine-1—carboxylic acid
8.21(m, 3H), 8.01(s, IH), 7.77(s,  8.21 (m, 3H), 8.01 (s, IH), 7.77 (s,
[6-(8-이소프로폭시- [6- (8-isopropoxy-
IH), 7.44(d, J=7.8 Hz, IH), 7.18- 퀴나졸린 -2-일아미노) - 503.1 IH), 7.44 (d, J = 7.8 Hz, IH), 7.18-quinazolin-2-ylamino) -503.1
7.28(m, 2H), 4.85(quin. , J=6.0 Hz,  7.28 (m, 2 H), 4.85 (quin., J = 6.0 Hz,
2-메틸 -1H- IH), 3.48(ιιι, 4H), 2.76(quin. , J=6.6  2-methyl-1H-IH), 3.48 (ιιι, 4H), 2.76 (quin., J = 6.6
벤즈이미다졸 -4-일] - Hz, IH), 2.54(m, 4H), 2.46(s, 3H), Benzimidazol-4-yl] -Hz, IH), 2.54 (m, 4H), 2.46 (s, 3H),
아미드 amides
1.35(d, J=6.0 Hz, 6H), 1.0  1.35 (d, J = 6.0 Hz, 6H), 1.0
]H丽 R (300 MHz, DMSO-de, δ ) ： ] H 丽 R (300 MHz, DMSO-de, δ) ：
4-메틸-피페라진 -1- lO.OKs, IH), 9.29(s, IH), 8.53(s,  4-methyl-piperazine-1-lO.OKs, IH), 9.29 (s, IH), 8.53 (s,
카르복실산 [6-(8-Carboxylic acids [6- (8-
IH), 8.15(s, 2H), 7.95(d, J=7.5 Hz, IH), 8.15 (s, 2H), 7.95 (d, J = 7.5 Hz,
클로로-퀴나졸린 -2-Chloro-quinazolin-2-
IH), 7.86(d, 7=8.1 Hz, IH) 7.66(s, 451.5 일아미노) -2-메틸 -1H- IH), 7.31(t, J=7.8 Hz, IH), 3.45- 벤즈이미다졸—4-일] - 3.49(m, 4H), 2.46(s, 3H)， 2.33- 아미드 IH), 7.86 (d, 7 = 8.1 Hz, IH) 7.66 (s, 451.5 monoamino) -2-methyl-1H-IH), 7.31 (t, J = 7.8 Hz, IH), 3.45- benzimidazole— 4-yl]-3.49 (m, 4H), 2.46 (s, 3H), 2.33- amide
2.37(m, 4H), 2.21(s, 3H)  2.37 (m, 4H), 2.21 (s, 3H)
¾ NMR (300 MHz, DMS0-d6, δ )： ¾ NMR (300 MHz, DMS0-d 6 , δ):
4-이소프로필- lO.OKs, IH), 9.29(s, IH), 8.54(s,  4-isopropyl-lO.OKs, IH), 9.29 (s, IH), 8.54 (s,
피페라진 -1-카르복실산 Piperazine-1-carboxylic acid
IH), 8.14(s, 2H), 7.95(d, J=7.5 Hz,  IH), 8.14 (s, 2H), 7.95 (d, J = 7.5 Hz,
[6-(8-클로로- [6- (8-chloro-
IH), 7.86(d, 7=7.8 Hz, IH) 7.66(s, IH), 7.86 (d, 7 = 7.8 Hz, IH) 7.66 (s,
퀴나졸린 -2-일아미노) - 479.2 Quinazolin-2-ylamino) -479.2
IH), 7.31(t, /=7.8 Hz, IH), 3.35- IH), 7.31 (t, / = 7.8 Hz, IH), 3.35-
2-메틸 -1H- 3.48(m, 4H), 2.71(quin., J=6.6 Hz, 2-methyl-1H-3.48 (m, 4H), 2.71 (quin., J = 6.6 Hz,
벤즈이미다졸 -4-일] - IH), 2.40-2.48(m, 7H), 1.00(d, J=6.6 아미드 Benzimidazol-4-yl] -IH), 2.40-2.48 (m, 7H), 1.00 (d, J = 6.6 amide)
Hz, 6H) 4-이소프로필- ¾ NMR (300 MHz, DMSOd6, δ )： Hz, 6H) 4-isopropyl-¾ NMR (300 MHz, DMSOd 6 , δ):
피페라진 -1—카르복실산 9.67(s, IH), 9.19(s, IH), 8.10-Piperazine-1—carboxylic acid 9.67 (s, IH), 9.19 (s, IH), 8.10-
[2-사이클로프로필 -6- 8.18(m, 3H)ᅳ 7.82(s, IH), 7.63- (8-메틸-퀴나졸린 -2- 7.71(m, 2H), 7.23(t, J=7.5 Hz, IH), 485.1 일아미노) -1H- 3.40-3.68(m, 8H), 2.85(m, IH), [2-cyclopropyl-6- 8.18 (m, 3H) H 7.82 (s, IH), 7.63- (8-methyl-quinazolin-2- 7.71 (m, 2H), 7.23 (t, J = 7.5 Hz, IH), 485.1 monoamino) -1H-3.40-3.68 (m, 8H), 2.85 (m, IH),
벤즈이미다졸 -4-일] - 2.64(s, 3H), 2.22(s, IH), 1.00- 아미드 1.02(m, 10H) Benzimidazol-4-yl] -2.64 (s, 3H), 2.22 (s, IH), 1.00-amide 1.02 (m, 10H)
모폴린—4—카르복실산 ¾ NMR (300 MHz, DMS0-d6) 10.02 (s, Morpholine—4—carboxylic acid ¾ NMR (300 MHz, DMS0-d 6 ) 10.02 (s,
[6-(8-클로로- IH), 9.29 (s, IH), 8.56 (brs, IH),  [6- (8-Chloro-IH), 9.29 (s, IH), 8.56 (brs, IH),
퀴나졸린— 2-일아미노) - 8.13 (s, IH), 7.95 (dd, J=7.5, 0.9 Quinazolin- 2-ylamino)-8.13 (s, IH), 7.95 (dd, J = 7.5, 0.9
438.4 438.4
2-메틸 -1H- Hz, IH), 7.86 (dd, J=7.5, 1.2 Hz, 2-methyl-1H- Hz, IH), 7.86 (dd, J = 7.5, 1.2 Hz,
벤즈이미다졸 -4-일] - IH), 7.31 (t, j=7.5 Hz, IH)， 3.63 (m, 아미드 4H), 3.45 (m, 4H), 2.46 (s, 3H) Benzimidazol-4-yl] -IH), 7.31 (t, j = 7.5 Hz, IH), 3.63 (m, amide 4H), 3.45 (m, 4H), 2.46 (s, 3H)
¾ NMR (300 MHz, DMS0-d6) 9.71 (s, ¾ NMR (300 MHz, DMS0-d 6 ) 9.71 (s,
1-이소프로필- IH), 9.49 (brs, IH) , 9.19 (s, IH),  1-isopropyl-IH), 9.49 (brs, IH), 9.19 (s, IH),
피페리딘 -4-카르복실산 8.21 (s, 2H), 8.18 (s, IH), 7.67 (dd, Piperidine-4-carboxylic acid 8.21 (s, 2H), 8.18 (s, IH), 7.67 (dd,
[2-메틸 -6-(8-메틸- j=22.8, 6.6 Hz, 2H), 7.23 (t, J=7.2 [2-Methyl-6- (8-methyl-j = 22.8, 6.6 Hz, 2H), 7.23 (t, J = 7.2
458.4 퀴나졸린 -2-일아미노) - Hz, IH), 4.05 (m, IH), 2.78 (m, 2H),  458.4 quinazolin-2-ylamino) -Hz, IH), 4.05 (m, IH), 2.78 (m, 2H),
1H-벤즈이미다졸 -4- 2.66 (m, IH), 2.49 (s, 3H), 2.46 (s, 일] -아미드 3H), 2.18 (m, 2H), 1.83 (ra, 2H), 1.63 1H-benzimidazole-4- 2.66 (m, IH), 2.49 (s, 3H), 2.46 (s, day] -amide 3H), 2.18 (m, 2H), 1.83 (ra, 2H), 1.63
(m, 2H), 0.98 (d, J=6.6 Hz, 6H)  (m, 2H), 0.98 (d, J = 6.6 Hz, 6H)
1-이소프로필- ¾ NMR (300 MHz, DMS0_d6) 9.61 (s, 1-isopropyl-¾ NMR (300 MHz, DMS0_d 6 ) 9.61 (s,
피페리딘 -4-카르복실산 IH), 9.18 (s, IH), 8.21 (s, IH), 7.98 Piperidine-4-carboxylic acid IH), 9.18 (s, IH), 8.21 (s, IH), 7.98
[2-사이클로프로필 -6- (brs, IH), 7.59 (d, J=7.5 Hz, IH), 528.2 (8-이소프로폭시- 7.24 (m, 2H), 4.83 (m, IH), 2.81 Cm, [2-cyclopropyl-6- (brs, IH), 7.59 (d, J = 7.5 Hz, IH), 528.2 (8-isopropoxy- 7.24 (m, 2H), 4.83 (m, IH), 2.81 Cm ,
퀴나졸린 -2-일아미노) - 5H), 2.17 (m, 4H), 1.72 (m, 5H), 1.32 IH-벤즈이미다졸 -4- (d, J=6.3 Hz, 6H), 1.02 (m, 4H), 0.99 일] -아미드 (d, J=6.6 Hz, 6H) Quinazolin-2-ylamino) -5H), 2.17 (m, 4H), 1.72 (m, 5H), 1.32 IH-benzimidazole-4- (d, J = 6.3 Hz, 6H), 1.02 (m, 4H), 0.99 day] -amide (d, J = 6.6 Hz, 6H)
¾ NMR (300 MHz, DMS0-dG, δ ) ： ¾ NMR (300 MHz, DMS0-d G , δ) ：
모폴린 -4-카르복실산 9.63(s, IH), 9.18(s, IH), 8.14(s, Morpholine-4-carboxylic acid 9.63 (s, IH), 9.18 (s, IH), 8.14 (s,
[2-사이클로프로필 -6ᅳ IH), 7.87(s, IH), 7.44(d, J=7.5 Hz, [2-cyclopropyl-6 ′ IH), 7.87 (s, IH), 7.44 (d, J = 7.5 Hz,
(8-이소프로폭시- IH), 7.17-7.27(m, 2H), 4.85(quin. , (8-isopropoxy-IH), 7.17-7.27 (m, 2H), 4.85 (quin.,
488.2 퀴나졸린 -2-일아미노) - J=5.7 Hz, IH)ᅳ 3.62-3.65(m, 4H),  488.2 quinazolin-2-ylamino) -J = 5.7 Hz, IH) ᅳ 3.62-3.65 (m, 4H),
1H-벤즈이미다졸 -4- 3.43-3.46(m, 4H), 2.12(quin. , J=6.0 1H-benzimidazole-4-3.43-3.46 (m, 4H), 2.12 (quin., J = 6.0
일] -아미드 Hz, IH), 1.33(d, J=6.3 Hz, 6H) , 1.00- 1.02(m, 4H) General] -amide Hz, IH), 1.33 (d, J = 6.3 Hz, 6H), 1.00- 1.02 (m, 4H)
¾ NMR (300 MHz, DMS0—d6) 10.03 (s, ¾ NMR (300 MHz, DMS0—d 6 ) 10.03 (s,
1-이소프로필- IH), 9.54 (brs, IH), 9.29 (s, IH),  1-isopropyl-IH), 9.54 (brs, IH), 9.29 (s, IH),
피페리딘 -4-카르복실산 8.57 (s, IH), 8.18 (s, IH), 8.01 Piperidine-4-carboxylic acid 8.57 (s, IH), 8.18 (s, IH), 8.01
[6-(8-클로로- (brs, IH), 7.96 (d, J=7.2 Hz, IH),  [6- (8-Chloro- (brs, IH), 7.96 (d, J = 7.2 Hz, IH),
퀴나졸린ᅳ 2-일아미노) - 7.87 (d, j=7.8 Hz, IH) , 7.31 (t, 478.5Quinazolin 졸 2-ylamino) -7.87 (d, j = 7.8 Hz, IH), 7.31 (t, 478.5
2-메틸 -1H- j=7.8 Hz, IH), 2.91 (m, 2H), 2.76 2-methyl-1H-j = 7.8 Hz, IH), 2.91 (m, 2H), 2.76
벤즈이미다졸 -4-일] - (m, IH), 2.53 (s, 3H), 2.24 (m, 2H), 아미드 11.84 Cm, 2H), 1.69 (m, 2H), 1.00 (d, Benzimidazol-4-yl]-(m, IH), 2.53 (s, 3H), 2.24 (m, 2H), amide 11.84 Cm, 2H), 1.69 (m, 2H), 1.00 (d,
j=6.6 Hz, 6H)  j = 6.6 Hz, 6H)
모폴린 -4-카르복실산 Morpholine-4-carboxylic acid
¾ NMR (300 MHz, DMS0-d6) δ ) ： ¾ NMR (300 MHz, DMS0-d 6) δ):
[2-메틸 -6-(8- 10.03(s, IH), 9.35(s, IH), 8.36(s, [2-methyl-6- (8-10.03 (s, IH), 9.35 (s, IH), 8.36 (s,
트리플루오로메틸- IH), 8.13-8.16(m, 2H), 7.42(t, J=7.8 472 퀴나졸린 -2-일아미노) - Hz, IH)ᅳ 3.62-3.65(m, 4H), 3.44- 1H-벤즈이미다졸 -4- 3.47(m, 4H), 2.46(s, 3H) Trifluoromethyl-IH), 8.13-8.16 (m, 2H), 7.42 (t, J = 7.8 472 quinazolin-2-ylamino)-Hz, IH) ᅳ 3.62-3.65 (m, 4H), 3.44- 1H-benzimidazole-4-3.47 (m, 4H), 2.46 (s, 3H)
일] -아미드 1-이소프로필- ]H NMR (300 MHz, DMS0-ds> δ ) ： General] -amide 1-isopropyl- ] H NMR (300 MHz, DMS0-d s> δ) ：
피페리딘 -4-카르복실산 9.13(s, IH), 8.28(s, 2H), 8.19(s, Piperidine-4-carboxylic acid 9.13 (s, IH), 8.28 (s, 2H), 8.19 (s,
[6-(8-이소프로폭시ᅳ IH), 7.91(s, IH), 7.57(m, IH), 7.45- 퀴나졸린 -2-일아미노) - 7.43(m, IH), 7.30-7.24(m, 2H), 3.60- 502.3[6- (8-Isopropoxyl IH), 7.91 (s, IH), 7.57 (m, IH), 7.45-quinazolin-2-ylamino) -7.43 (m, IH), 7.30-7.24 (m , 2H), 3.60- 502.3
2-메틸 -1H- 3.75(m, 3H), 3.17(m, 2H), 2.85(m, 2-methyl-1H-3.75 (m, 3H), 3.17 (m, 2H), 2.85 (m,
벤즈이미다졸 -4-일] - IH), 2.61(s, 3H), 2.27-2.17(m, 4H)， Benzimidazol-4-yl] -IH), 2.61 (s, 3H), 2.27-2.17 (m, 4H),
아미드 1.45-1.38(m, 12H) Amide 1.45-1.38 (m, 12H)
4-이소프로필- 4-isopropyl-
¾ NMR (300 MHz, DMS0-d6, δ ) ： ¾ NMR (300 MHz, DMS0-d 6 , δ) ：
피페라진 -1-카르복실산 Piperazine-1-carboxylic acid
10.02(s, IH), 9.35(s, IH), 8.33(s,  10.02 (s, IH), 9.35 (s, IH), 8.33 (s,
[2-메틸 -6-(8- IH), 8.13-8.16(m, 4H), 7.57(s, IH) ,  [2-Methyl-6- (8-IH), 8.13-8.16 (m, 4H), 7.57 (s, IH),
트리플루오로메틸- 513.3 Trifluoromethyl- 513.3
7.42(t, J=7.5 Hz, IH), 2.67-2.72(m,  7.42 (t, J = 7.5 Hz, IH), 2.67-2.72 (m,
퀴나졸린 -2-일아미노) - IH), 2.46(s, 3H), 0.99(d, J=6.3 Hz, Quinazolin-2-ylamino) -IH), 2.46 (s, 3H), 0.99 (d, J = 6.3 Hz,
1H-벤즈이미다졸 -4- 6H) 1H-benzimidazole-4-6H)
일] -아미드 General] -amide
4-(1-하이드록시 -1- JH NMR (300 MHz, DMS0-d6) 9.68 (s, 4- (1-hydroxy-1- J H NMR (300 MHz, DMS0-d 6 ) 9.68 (s,
메틸-에틸)ᅳ피페리딘ᅳ IH), 9.19 (s, IH), 8.22 (s, IH), 8.18 Methyl-ethyl) ᅳ piperidine ᅳ IH), 9.19 (s, IH), 8.22 (s, IH), 8.18
1-카르복실산 [2-메틸- (s, IH), 7.67 (dd, j=14.7, 6.6 Hz, 1-carboxylic acid [2-methyl- (s, IH), 7.67 (dd, j = 14.7, 6.6 Hz,
6-(8-메틸-퀴나졸린 -2- 2H), 7.22 (t, j=7.5 Hz, IH), 4.14 474.4 일아미노) -1H- (brs, IH), 2.63 (s, 3H), 2.56 (s, 6- (8-methyl-quinazolin-2-2H), 7.22 (t, j = 7.5 Hz, IH), 4.14 474.4 monoamino) -1H- (brs, IH), 2.63 (s, 3H), 2.56 ( s,
벤즈이미다졸 -4—일 ] - 3H), 1.63 (d, j=12.3 Hz, 4H), 1.26 Benzimidazole-4—yl] -3H), 1.63 (d, j = 12.3 Hz, 4H), 1.26
아미드 (m, IH), 1.00 (s, 6H) Amide (m, IH), 1.00 (s, 6H)
테트라하이드로-피란- ¾. NMR (300 MHz, DMS0-d6) 12.12 (brs, Tetrahydro-pyran- 3/4. NMR (300 MHz, DMS0-d 6 ) 12.12 (brs,
4-카르복실산 [2-메틸- IH), 9.73 (s, IH), 9.53 (brs, IH), 4-carboxylic acid [2-methyl-IH), 9.73 (s, IH), 9.53 (brs, IH),
6-(8—메틸-퀴나졸린 -2- 9.20 (s, IH), 8.21 (brs, IH), 8.19 417.5 일아미노) -1H- (s, IH), 7.68 (dd, j=15.6, 7.8 Hz, 6- (8—methyl-quinazolin-2- 9.20 (s, IH), 8.21 (brs, IH), 8.19 417.5 ylamino) -1H- (s, IH), 7.68 (dd, j = 15.6, 7.8 Hz ,
벤즈이미다졸 -4-일] - 2H), 7.23 (t, j=7.8 Hz, IH), 3.91 (d, 아미드 J=11.4 Hz, 2H), 2.63 (s, 3H), 1.71 Benzimidazol-4-yl] -2H), 7.23 (t, j = 7.8 Hz, IH), 3.91 (d, Amide J = 11.4 Hz, 2H), 2.63 (s, 3H), 1.71
(m, 4H)  (m, 4H)
테트라하이드로-퓨란- ¾ NMR (300 MHz, DMS0-d6) 9.80 (s, Tetrahydro-furan- ¾ NMR (300 MHz, DMS0-d 6 ) 9.80 (s,
3-카르복실산 [2-메틸- IH), 9.74 (s, IH), 9.20 (s, IH), 8.19  3-carboxylic acid [2-methyl-IH), 9.74 (s, IH), 9.20 (s, IH), 8.19
6-(8-메틸-퀴나졸린 -2- (s, IH), 8.15 (s, IH), 7.68 (dd,  6- (8-methyl-quinazolin-2- (s, IH), 8.15 (s, IH), 7.68 (dd,
72 403.4 일아미노) -1H- J=15.6, 7.5 Hz, 2H), 7.23 (t, J=8.4  72 403.4 monoamino) -1 H-J = 15.6, 7.5 Hz, 2H), 7.23 (t, J = 8.4
벤즈이미다졸 -4-일] - Hz, IH), 3.96 (t, J=7.8 Hz, IH), 3.75 아미드 (m, 4H), 2.62 (S> 3H), 2.08 (m, 2H) Benzimidazol-4-yl] -Hz, IH), 3.96 (t, J = 7.8 Hz, IH), 3.75 amide (m, 4H), 2.62 ( S> 3H), 2.08 (m, 2H)
4-메틸- ]H 匪 R (300 MHz, DMS0-d6) 9.76 (s, 4-methyl- ] H 匪 R (300 MHz, DMS0-d 6 ) 9.76 (s,
테트라하이드로-피란- IH), 9.20 (s, IH), 8.92 (brs, IH),  Tetrahydro-pyran-IH), 9.20 (s, IH), 8.92 (brs, IH),
4-카르복실산 [2-메틸- 8.18 (brs, IH), 8.11 (s, IH) , 7.68  4-carboxylic acid [2-methyl-8.18 (brs, IH), 8.11 (s, IH), 7.68
73 6-(8-메틸-퀴나졸린 -2- (dd, J=15.9, 7.8 Hz, 2H), 7.23 (t, 431.5 일아미노) -1H- J=7.5 Hz, IH), 3.67 (m, 2H) , 3.55 (m, 벤즈이미다졸—4-일 ] - 2H), 2.63 (s, 3H), 2.10 (m, 2H), 1.53 아미드 (m, 2H), 1.33 (s, 3H)  73 6- (8-Methyl-quinazolin-2- (dd, J = 15.9, 7.8 Hz, 2H), 7.23 (t, 431.5 monoamino) -1 H-J = 7.5 Hz, IH), 3.67 (m, 2H ), 3.55 (m, benzimidazol—4-yl]-2H), 2.63 (s, 3H), 2.10 (m, 2H), 1.53 amide (m, 2H), 1.33 (s, 3H)
¾ NMR (300 MHz, DMS0-d6, δ ) ： ¾ NMR (300 MHz, DMS0-d 6 , δ) ：
2， 6-다이메틸 -모폴린- 9.73(s, IH), 9.20(s, IH), 8.24(m,  2, 6-dimethyl-morpholine- 9.73 (s, IH), 9.20 (s, IH), 8.24 (m,
4-카르복실산 [2-메틸- 2H), 8.14(br s, IH), 7.77(br s, IH) ,  4-carboxylic acid [2-methyl-2H), 8.14 (br s, IH), 7.77 (br s, IH),
6-(8-메틸-퀴나졸린 -2- 6- (8-methyl-quinazolin-2-
74 7.64-7.71(ra, 2H), 7.23(t, IH), 3.62- 446 일아미노) -1H- 3.65(m, 4H)y 3.44— 3.47(m, 4H), 74 7.64-7.71 (ra, 2H), 7.23 (t, IH), 3.62- 446 monoamino) -1H-3.65 (m, 4H) y 3.44-3.47 (m, 4H),
벤즈이미다졸 -4-일 ] - 2.64(s, 3H), 2.47(s, 3H), 1.22 (d,  Benzimidazol-4-yl] -2.64 (s, 3H), 2.47 (s, 3H), 1.22 (d,
아미드  amides
6H) 테트라하이드로-피란- ¾ NMR (300 MHz, DMS0-d6) 9.71 (s, 6H) Tetrahydro-pyran- ¾ NMR (300 MHz, DMS0-d 6 ) 9.71 (s,
4ᅳ카르복실산 [2- IH), 9.38 (brs, IH), 9.20 (s, IH),  4'carboxylic acid [2-IH), 9.38 (brs, IH), 9.20 (s, IH),
사이클로프로필 -6-(8- 8.21 (brs, IH), 8.09 (s, IH), 7.67  Cyclopropyl-6- (8- 8.21 (brs, IH), 8.09 (s, IH), 7.67
77 메틸-퀴나졸린 -2- (dd, J=15.6, 7.5 Hz, 2H), 7.23 (t, 443.5 일아미노) -1H- J=7.2 Hz, IH), 3.91 (d, J=ll.l Hz,  77 Methyl-quinazolin-2- (dd, J = 15.6, 7.5 Hz, 2H), 7.23 (t, 443.5 monoamino) -1 H-J = 7.2 Hz, IH), 3.91 (d, J = ll.l Hz ,
벤즈이미다졸ᅳ 4-일] - 4H), 2.63 (s, 3H), 2.12 (m, IH), 1.72 아미드 (m, 4H), 1.03 (d, J=7.2 Hz, 4H)  Benzimidazolazole 4-yl]-4H), 2.63 (s, 3H), 2.12 (m, IH), 1.72 amide (m, 4H), 1.03 (d, J = 7.2 Hz, 4H)
¾ NMR (300 MHz, DMSOd (；， δ ) ：  ¾ NMR (300 MHz, DMSOd (; δ) ：
N-[2-사이클로프로필- 12.20(s, IH), 10.04(s, IH), 9.78(s,  N- [2-cyclopropyl- 12.20 (s, IH), 10.04 (s, IH), 9.78 (s,
6- (8—메틸-퀴나졸린 -2- IH), 9.20(s, IH), 8.33(s, IH),  6- (8—methyl-quinazolin-2-IH), 9.20 (s, IH), 8.33 (s, IH),
일아미노) -1H- Monoamino) -1H-
78 8.15(s, IH), 7.71-7.63(m, 2H), 458.2 벤즈이미다졸 -4—일 ] -2ᅳ 78 8.15 (s, IH), 7.71-7.63 (m, 2H), 458.2 benzimidazole-4-yl] -2 ᅳ
7.23(t, J=7.5Hz, IH), 3.73-3.44(m,  7.23 (t, J = 7.5 Hz, IH), 3.73-3.44 (m,
모폴린 -4-일- 6H), 2.65(s, 3H), 2.59-2.56 (m, 4H) ,  Morpholin-4-yl-6H), 2.65 (s, 3H), 2.59-2.56 (m, 4H),
아세트아미드  Acetamide
2·14-2.07(ιιι, IH), 1.04-1.02(m, 4H)  2 · 14-2.07 (ιιι, IH), 1.04-1.02 (m, 4H)
4-메틸- 4-methyl-
]H NMR (300 MHz, DMSO, δ ) ： ] H NMR (300 MHz, DMSO, δ) ：
테트라하이드로ᅳ피란- 9.77(s, IH), 9.20(s, IH), 8.95(br s,  Tetrahydrocyanpyran- 9.77 (s, IH), 9.20 (s, IH), 8.95 (br s,
4-카르복실산 [2- IH), 8.31(s, IH), 8.19(s, IH),  4-carboxylic acid [2-IH), 8.31 (s, IH), 8.19 (s, IH),
사이클로프로필 -6-(8- Cyclopropyl-6- (8-
80 8.05(s, IH), 7.71-7.64(m, 2H), 457.1 메틸-퀴나졸린 -2- 7.23(t, J=7.5Hz, IH), 2.63(s, 3H), 80 8.05 (s, IH), 7.71-7.64 (m, 2H), 457.1 methyl-quinazolin-2-7.23 (t, J = 7.5 Hz, IH), 2.63 (s, 3H),
일아미노)— 1H- 2.20-2.06(ni, 3H), 1.54(m, 2H)' Monoamino) — 1H-2.20-2.06 (ni, 3H), 1.54 (m, 2H) ''
벤즈이미다졸 _4_일]_ Benzimidazole _ 4 _day] _
1.33(s, 3H), 1.04-1.01(m, 4H)  1.33 (s, 3 H), 1.04-1.01 (m, 4 H)
아미드  amides
4ᅳ(2:2，2- ¾ NMR (300 MHz, DMSO, δ ) ：  4 ᅳ (2: 2, 2-¾ NMR (300 MHz, DMSO, δ) ：
트리플루오로-에틸) - 9.72(s, IH), 9.20(s, IH), 8.24(s,  Trifluoro-ethyl)-9.72 (s, IH), 9.20 (s, IH), 8.24 (s,
81 525.2 피페라진 -1-카르복실산 IH), 8.12(m, 2H), 7.79(s, IH), 7.71- 81 525.2 Piperazine-1-carboxylic acid IH), 8.12 (m, 2H), 7.79 (s, IH), 7.71-
[2-사이클로프로필 -6- 7.63(m, 2H), 7.23(t, J=7.5Hz, IH), ( 8-메틸-퀴나졸린 -2- 3.48(111， 4H), 3.29-3.17(m, 2H), 2.67- 일아미노) -1H- 2.63(m, 7H), 2.120)1， IH), 1.02(m, 4H) 벤즈이미다졸 -4—일] - 아미드 [2-cyclopropyl-6- 7.63 (m, 2H), 7.23 (t, J = 7.5 Hz, IH), (8-Methyl-quinazolin-2- 3.48 (111, 4H), 3.29-3.17 (m, 2H), 2.67-ylamino) -1H-2.63 (m, 7H), 2.120) 1, IH), 1.02 ( m, 4H) benzimidazole-4—yl] -amide
¾ 匪 R (300 MHz, DMS0, δ ) ：  ¾ 匪 R (300 MHz, DMS0, δ) ：
1-[2-메틸 -6-(8-메틸- 9.70(s, IH), 9.24-9.20(m, 2H),  1- [2-methyl-6- (8-methyl-9.70 (s, IH), 9.24-9.20 (m, 2H),
퀴나졸린 -2-일아미노) - 8.66(br s, IH), 8.25(s, IH), 8.10(s,  Quinazolin-2-ylamino)-8.66 (br s, IH), 8.25 (s, IH), 8.10 (s,
83 1H-벤즈이미다졸 -4- IH), 7.71-7.64(m, 2H), 7.36-7.34(m, 509.3 일] -3-(4-모폴린 -4-일- 2H), 7.23(t, J=7.5Hz, IH), 6.90- 페닐) -우레아 6.87(iii, 2H), 3.72(III, 4H), 3.01(m,  83 1H-benzimidazole-4-IH), 7.71-7.64 (m, 2H), 7.36-7.34 (m, 509.3 days) -3- (4-morpholin-4-yl-2H), 7.23 (t, J = 7.5 Hz, IH), 6.90-phenyl) -urea 6.87 (iii, 2H), 3.72 (III, 4H), 3.01 (m,
4H), 2.65(s, 3H)  4H), 2.65 (s, 3H)
¾ NM (300 MHz, DMS0-d6) 9.86 (s, ¾ NM (300 MHz, DMS0-d 6 ) 9.86 (s,
N-[2-메틸 -6-(8-메틸- IH), 9.25 (s, IH), 7.98 (s, IH), 7.70 - 퀴나졸린 -2-일아미노) - (dd, J=17.1, 7.2 Hz, 4H), 7.25 (t,  N- [2-Methyl-6- (8-methyl-IH), 9.25 (s, ih), 7.98 (s, ih), 7.70-quinazolin-2-ylamino)-(dd, J = 17.1, 7.2 Hz, 4H), 7.25 (t,
84 1H-벤즈이미다졸 -4- 494.4  84 1H-benzimidazole-4- 494.4
J=6.9 Hz, IH)ᅳ 7.06 (brs, 2H), 3.74  J = 6.9 Hz, IH) ᅳ 7.06 (brs, 2H), 3.74
일] -4-모폴린—4-일- (s, 4H), 3.69 (s, 4H), 3.20 (s, 3H), 벤즈아미드  General] -4-morpholine—4-yl- (s, 4H), 3.69 (s, 4H), 3.20 (s, 3H), benzamide
2.71 (s, 3H)  2.71 (s, 3 H)
]H NMR (300 MHz, DMS0-d6) 12.14 (s, ] H NMR (300 MHz, DMS0-d 6 ) 12.14 (s,
IH), 9.82 (s, IH), 9.21 (s, IH),  IH), 9.82 (s, IH), 9.21 (s, IH),
N— [2-사이클로프로필- 8.25 (s, IH), 7.93 (s, IH), 7.76 (d,  N— [2-cyclopropyl-8.25 (s, IH), 7.93 (s, IH), 7.76 (d,
6-(8—메틸-퀴나졸린 -2- J=8.7 Hz, IH), 7.68 (dd, J=17.1, 7.8 일아미노) -1H- 6- (8—Methyl-quinazolin-2-J = 8.7 Hz, IH), 7.68 (dd, J = 17.1, 7.8 monoamino) -1 H-
85 Hz, IH), 7.23 (t, J=7.2 Hz, IH), 7.05 520.3 벤즈이미다졸—4-일] -4- (d, J=8.7 Hz, 2H), 6.94 (d, J=8.7 Hz, 모폴린 -4-일- 2H), 3.72 Cm, 8H), 2.64 (s, 3H), 2.64 벤즈아미드 85 Hz, IH), 7.23 (t, J = 7.2 Hz, IH), 7.05 520.3 benzimidazol—4-yl] -4- (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.7 Hz , Morpholin-4-yl-2H), 3.72 Cm, 8H), 2.64 (s, 3H), 2.64 benzamide
(s, 3H), 2.13 (m, IH), 1.03 (d, J =6.0  (s, 3H), 2.13 (m, IH), 1.03 (d, J = 6.0
Hz, 4H) ]H 丽 R (300丽 z, DMSO-dc) 12.24 (s, Hz, 4H) ] H 丽 R (300 丽 z, DMSO-dc) 12.24 (s,
3-플루오로 -N- [2-메틸- IH), 10.33 (s, IH), 9.85 (d, J=17.4  3-fluoro-N- [2-methyl-IH), 10.33 (s, IH), 9.85 (d, J = 17.4
6-(8-메틸-퀴나졸린 -2- Hz, IH), 9.22 (s, IH), 8.38 (s, IH), 일아미노)— 1H- 8.01 (s, IH), 7.69 (dd, J=15.9, 7.5  6- (8-methyl-quinazolin-2-Hz, IH), 9.22 (s, IH), 8.38 (s, IH), monoamino)-1H-8.01 (s, IH), 7.69 (dd, J = 15.9, 7.5
86 512.4 벤즈이미다졸 -4-일 ] -5- Hz, 2H), 7.43 (s, IH), 7.24 (m, 2H), 모폴린 -4—일- 7.00 (m, IH), 3.74 (m, 4H), 3.28 (s, 벤즈아미드 4H), 3.25 (s, 3H), 2.63 (d, J=5.4 Hz,  86 512.4 benzimidazol-4-yl] -5- Hz, 2H), 7.43 (s, IH), 7.24 (m, 2H), morpholine-4—yl- 7.00 (m, IH), 3.74 (m, 4H), 3.28 (s, benzamide 4H), 3.25 (s, 3H), 2.63 (d, J = 5.4 Hz,
3H)  3H)
]H NMR (300 MHz, DMSOd6) 9.82 (s, ] H NMR (300 MHz, DMSOd 6 ) 9.82 (s,
N-[2-사이클로프로필- IH), 9.22 (d, J-1.5 Hz, IH), 8.47 (s,  N- [2-cyclopropyl-IH), 9.22 (d, J-1.5 Hz, IH), 8.47 (s,
6- (8-메틸—퀴나졸린 -2- IH), 8.27 (brs, IH), 7.93 (brs, IH), 일아미노) -1H- 7.68 (dd, J=17.7, 8.1 Hz, 2H), 7.44  6- (8-methyl-quinazolin-2-IH), 8.27 (brs, IH), 7.93 (brs, IH), monoamino) -1H-7.68 (dd, J = 17.7, 8.1 Hz, 2H), 7.44
87 538.5 벤즈이미다졸—4ᅳ일] -3- (s, IH), 7.24 (m, 2H), 6.99 (d,  87 538.5 benzimidazole—4 yl] -3- (s, IH), 7.24 (m, 2H), 6.99 (d,
플루오로 -5-모폴린ᅳ 4- J=12.6 Hz, IH), 3.74 (m, 4H), 3.24  Fluoro-5-morpholine ᅳ 4- J = 12.6 Hz, IH), 3.74 (m, 4H), 3.24
일ᅳ벤즈아미드 Cm, 2H), 2.63 (s, 3H), 2.12 (m, IH),  Iljanbenzamide Cm, 2H), 2.63 (s, 3H), 2.12 (m, IH),
1.02 (d, J=6.0 Hz, 4H)  1.02 (d, J = 6.0 Hz, 4H)
¾ 匪 R (300 MHz, DMSO, δ ) ：  ¾ 匪 R (300 MHz, DMSO, δ) ：
모폴린—4-설폰산 [2- 12.20(s, IH), 9.89(s, IH) ' 9.22(s,  Morpholine—4-sulfonic acid [2- 12.20 (s, IH), 9.89 (s, IH) '9.22 (s,
사이클로프로필ᅳ6-(8- IH), 8.36(br s, IH), 8.12(s, IH),  Cyclopropyl ᅳ 6- (8-IH), 8.36 (br s, IH), 8.12 (s, IH),
메틸-퀴나졸린 -2- Methyl-Quinazoline-2-
88 7.73-7.66(m, 2H), 7.57(s, IH), 480.3 일아미노) -1H- 7.25(t, J=7.8Hz, IH), 3.49(m, 4H), 88 7.73-7.66 (m, 2H), 7.57 (s, IH), 480.3 monoamino) -1H-7.25 (t, J = 7.8 Hz, IH), 3.49 (m, 4H),
벤즈이미다졸 -4-일] - 3.11(m, 4H), 2.66(s, 3H), 2.12(m,  Benzimidazol-4-yl] -3.11 (m, 4H), 2.66 (s, 3H), 2.12 (m,
아미드  amides
IH), 1.05(m, 4H)  IH), 1.05 (m, 4H)
1-[2—사이클로프로필- ¾ NMR (300 MHz, DMSO, δ ) ：  1- [2—cyclopropyl- ¾ NMR (300 MHz, DMSO, δ) ：
89 6_(8-메틸-퀴나졸린 -2- 12.08(br s, IH), 9.71(s, IH), 9.43(s, 535.5 일아미노) -1H- 1H)' 9.19(s, IH), 8.57(br s, IH), 벤즈이미다졸 -4-일] -3- 8.30-8.21(m, 2H), 8.04(s, 1H)， 7.71- (3-모폴린 -4-일-페닐) - 7.63(m, 2H), 7.28— 7.20 (m, 2H), 우레아 7.11(t, J=8.1Hz, 1Η)' 6.82(d, 89 6_ (8-Methyl-quinazolin-2-12.08 (br s, IH), 9.71 (s, IH), 9.43 (s, 535.5 monoamino) -1H-1H) '9.19 (s, IH), 8.57 ( br s, IH), Benzimidazol-4-yl] -3-8.30-8.21 (m, 2H), 8.04 (s, 1H), 7.71- (3-morpholin-4-yl-phenyl) -7.63 (m, 2H), 7.28 — 7.20 (m, 2H), Urea 7.11 (t, J = 8.1 Hz, 1Η) '6.82 (d,
J=7.8Hz, IH), 6.56(d, J=8.1Hz, IH),  J = 7.8 Hz, IH), 6.56 (d, J = 8.1 Hz, IH),
3.74(m, 4H), 3.07(m, 4  3.74 (m, 4 H), 3.07 (m, 4
¾醒 R (300 MHz, DMS0-ds) 10.22 (s, ¾ 醒 R (300 MHz, DMS0-d s ) 10.22 (s,
1ᅡ[2-메틸-6-(8-메틸- IH), 9.91 (s, IH), 9.23 (s, IH) , 9.17 퀴나졸린 -2-일아미노) - 1 '[2-Methyl-6- (8-methyl-IH), 9.91 (s, IH), 9.23 (s, IH), 9.17 quinazolin-2-ylamino)
90 (s, IH), 8.77 (s, IH), 8.38 (m, 2H), 410.3 1H-벤즈이미다졸 -4- 7.67 (m, 4H), 7.25 (t, J=7.5 Hz, IH), 일] -니코틴아미드 90 (s, IH), 8.77 (s, IH), 8.38 (m, 2H), 410.3 1H-benzimidazole-4- 7.67 (m, 4H), 7.25 (t, J = 7.5 Hz, IH), day Nicotinamide
3.21 (s, 3H), 2.66 (s, 3H)  3.21 (s, 3H), 2.66 (s, 3H)
¾ NMR (300 MHz, DMSO, 5 ) ：  ¾ NMR (300 MHz, DMSO, 5) ：
9.73(s, IH), 9.39(s, IH), 9.20(s,  9.73 (s, IH), 9.39 (s, IH), 9.20 (s,
1- [2-메틸ᅳ 6- (8-메틸- IH), 8.73(s, IH), 8.31(s, IH),  1- [2-methyl ᅳ 6- (8-methyl-IH), 8.73 (s, IH), 8.31 (s, IH),
퀴나졸린ᅳ 2-일아미노) - 8.17(s, IH), 8.11(s, IH) , 7.71- Quinazolin 졸 2-ylamino)-8.17 (s, IH), 8.11 (s, IH), 7.71-
91 1H-벤즈이미다졸 -4- 509.2 91 1H-benzimidazole-4-509.2
7.64(m, 2H), 7.29(s, IH), 7.23(t,  7.64 (m, 2H), 7.29 (s, IH), 7.23 (t,
일] -3-(3-모폴린ᅳ4-일- J =7.8Hz, IH), 7.11(t, J=8.1Hz, IH),  General] -3- (3-morpholinyl4-yl-J = 7.8Hz, IH), 7.11 (t, J = 8.1Hz, IH),
페닐) -우레아  Phenyl) -urea
6.79(d, J=8.1Hz, IH), 6.56(d,  6.79 (d, J = 8.1 Hz, IH), 6.56 (d,
J=8.1Hz, IH), 3.75-3.72(m, 4H) ,  J = 8.1 Hz, IH), 3.75-3.72 (m, 4H),
¾ NMR (300 MHz, 10.30 (s,  ¾ NMR (300 MHz, 10.30 (s,
N-[2-사이클로프로필- IH), 9.86 (s, IH), 9.20 (d, J=11.7  N- [2-cyclopropyl-IH), 9.86 (s, IH), 9.20 (d, J = 11.7
6-(8-메틸-퀴나졸린 -2- Hz, 2H), 8.77 (s, IH) , 8.29 (ηι, 3H),  6- (8-methyl-quinazolin-2-Hz, 2H), 8.77 (s, ih), 8.29 (ηι, 3H),
93 일아미노) -1H- 463.3  93 ylamino) -1H-463.3
7.97 (brs, IH), 7.65 On, 3H), 7.25  7.97 (brs, IH), 7.65 On, 3H), 7.25
벤즈이미다졸 -4-일] - (s, IH), 2.64 (s, 3H), 2.12 (m, IH), 니코틴아미드  Benzimidazol-4-yl]-(s, IH), 2.64 (s, 3H), 2.12 (m, IH), nicotinamide
1.03 (s, 4H) :H NMR (300 MHz, DMS0-d6) 9.85 (s, 1.03 (s, 4 H) : H NMR (300 MHz, DMS0-d 6 ) 9.85 (s,
N-[2-사이클로프로필- IH), 9.22 (s, IH), 8.27 (s, IH), 8.14  N- [2-cyclopropyl-IH), 9.22 (s, IH), 8.27 (s, IH), 8.14
6-(8-메틸-퀴나졸린 -2- (s, 1H>, 7.99 (d, J=8.1 Hz, 2H), 7.53 일아미노) -1H- (dd, J=17.7, 8.1 Hz, 2H), 7.48 (d,  6- (8-methyl-quinazolin-2- (s, 1H>, 7.99 (d, J = 8.1 Hz, 2H), 7.53 monoamino) -1H- (dd, J = 17.7, 8.1 Hz, 2H), 7.48 (d,
95 534.4 벤즈이미다졸 -4-일] -4- J=8.1 Hz, 2H), 7.24 (t, J=7.8 Hz,  95 534.4 benzimidazol-4-yl] -4- J = 8.1 Hz, 2H), 7.24 (t, J = 7.8 Hz,
모폴린 -4-일메틸- IH), 3.57 (m, 6H), 2.64 (s, 3H),  Morpholin-4-ylmethyl-IH), 3.57 (m, 6H), 2.64 (s, 3H),
벤즈아미드 2.37 (m, 4H), 2.12 (m, IH) , 1.03 (d,  Benzamide 2.37 (m, 4H), 2.12 (m, IH), 1.03 (d,
J=6.3 Hz, 4H)  J = 6.3 Hz, 4H)
¾ NMR (300 MHz, DMS0-d6) 9.79 (s, ¾ NMR (300 MHz, DMS0-d 6 ) 9.79 (s,
N-[2-사이클로프로필- IH), 9.21 (s, IH), 8.24 (s, IH), 8.16  N- [2-cyclopropyl-IH), 9.21 (s, IH), 8.24 (s, IH), 8.16
6-(8-메틸-퀴나졸린 -2- (s, IH), 7.90 (d, J=8.4 Hz, 2H), 7.68 일아미노) -1H- (dd, J=17.1, 7.8 Hz, 2H), 7.24 (t,  6- (8-methyl-quinazolin-2- (s, IH), 7.90 (d, J = 8.4 Hz, 2H), 7.68 monoamino) -1H- (dd, J = 17.1, 7.8 Hz, 2H), 7.24 (t,
96 533.3 벤즈이미다졸 -4-일 ] -4- J=7.2 Hz, IH), 7.03 (d, J=9.0 Hz,  96 533.3 benzimidazol-4-yl] -4- J = 7.2 Hz, IH), 7.03 (d, J = 9.0 Hz,
(4-메틸-피페라진 -1- 2H), 2.64 (s, 3H), 2.44 (m, 4H) ,  (4-methyl-piperazine-1-2H), 2.64 (s, 3H), 2.44 (m, 4H),
일) -벤즈아미드 2.22 (s, 3H), 2.13 (m, IH) , 1.03 (d,  I) -benzamide 2.22 (s, 3H), 2.13 (m, IH), 1.03 (d,
J=6.6 Hz, 4H)  J = 6.6 Hz, 4H)
]H NMR (300 MHz, DMSO, δ ) ： ] H NMR (300 MHz, DMSO, δ) ：
모폴린 -4-카르복실산  Morpholine-4-carboxylic acid
9.99(s, IH), 9.24(s, IH), 8.55(s,  9.99 (s, IH), 9.24 (s, IH), 8.55 (s,
[2-사이클로프로필 -1- IH), 8.37(s, IH), 7.86(s, IH), 7.75- 메틸 -6-(8-메틸- [2-cyclopropyl-1-IH), 8.37 (s, IH), 7.86 (s, IH), 7.75-methyl-6- (8-methyl-
97 7.67(m, 2H), 7.27(t, J=7.2Hz, IH), 458.3 퀴나졸린 -2-일아미노) - 3.87(s, 3H), 3.65-3 ·62(πι, 4H), 97 7.67 (m, 2H), 7.27 (t, J = 7.2 Hz, IH), 458.3 quinazolin-2-ylamino)-3.87 (s, 3H), 3.65-362 (πι, 4H),
1H-벤즈이미다졸 -4- 3.47(iii, 4H), 2.67(s, 3H), 2.31(m,  1H-benzimidazole-4-3.47 (iii, 4H), 2.67 (s, 3H), 2.31 (m,
일] -아미드  General] -amide
IH), 1.14(m, 4H) 2,6-다이메틸 -모폴린- 4-카르복실산 [2- ]H NMR (300 MHz, DMS0-d6) 12.01 (br, 사이클로프로필 -6-(8- IH), 9.73 (s, 2H), 9.21 (s, 2H), 7.27 IH), 1.14 (m, 4H) 2,6-dimethyl-morpholine 4-carboxylic acid [2- ] H NMR (300 MHz, DMS0-d 6 ) 12.01 (br, cyclopropyl-6- (8-IH), 9.73 (s, 2H ), 9.21 (s, 2H), 7.27
101 메틸-퀴나졸린 -2- (m, 2H), 7.25 (m, IH), 4.02 (m, 2H), 472 일아미노) -1H- 3.57 (m, 2H), 2.66 (s, 3H) , 2.15(m, 벤즈이미다졸 -4-일] - IH), 1.27-1.02 (m, 10H)  101 Methyl-quinazolin-2- (m, 2H), 7.25 (m, IH), 4.02 (m, 2H), 472 monoamino) -1H-3.57 (m, 2H), 2.66 (s, 3H), 2.15 (m, benzimidazol-4-yl] -IH), 1.27-1.02 (m, 10H)
아미드  amides
¾ NMR (300 MHz, DMS0-ds) 9.89 (s, ¾ NMR (300 MHz, DMS0-d s ) 9.89 (s,
모폴린—4-카르복실산  Morpholine—4-carboxylic acid
IH), 9.25 (s, IH), 8.45 (br s, IH),  IH), 9.25 (s, IH), 8.45 (br s, IH),
[2-이소프로필 -6-(8- 8.32 (s, IH), 7.88 (s, IH), 7.76 (dd, 메틸-퀴나졸린 -2- [2-Isopropyl-6- (8- 8.32 (s, IH), 7.88 (s, IH), 7.76 (dd, methyl-quinazolin-2-
102 J=16.8, 7.8 Hz, 2H), 7.28 (t, J=7.5 446 일아미노) -1H- Hz, IH), 3.66 (m, 4H), 3.55 (m, 4H), 벤즈이미다졸—4-일] - 3.15 Cm, IH), 2.69 (s, 3H), 1.41 (d, 아미드 102 J = 16.8, 7.8 Hz, 2H), 7.28 (t, J = 7.5 446 monoamino) -1H- Hz, IH), 3.66 (m, 4H), 3.55 (m, 4H), benzimidazole—4- General]-3.15 Cm, IH), 2.69 (s, 3H), 1.41 (d, amide
J=6.6 Hz, 6H)  J = 6.6 Hz, 6H)
¾ NMR (300 MHz, DMSO, δ ) ：  ¾ NMR (300 MHz, DMSO, δ) ：
1-[2-사이클로프로필- 12.04(br s, IH), 9.67(s, IH), 9.28(br  1- [2-cyclopropyl- 12.04 (br s, IH), 9.67 (s, IH), 9.28 (br
6-(8-메틸-퀴나졸린 -2ᅳ s, IH), 9.19(s, IH), 8.30(s, IH),  6- (8-methyl-quinazolin-2 ′ s, IH), 9.19 (s, IH), 8.30 (s, IH),
일아미노) -1H- 8.26(s, IH), 8.03(s, IH), 7.71- Monoamino) -1H-8.26 (s, IH), 8.03 (s, IH), 7.71-
103 535.5 벤즈이미다졸 -4-일 ] -3- 7.63(III, 2H), 7.37-7.34(ni, 2H), 103 535.5 benzimidazol-4-yl] -3- 7.63 (III, 2H), 7.37-7.34 (ni, 2H),
(4-모플린 -4ᅳ일—페닐) - 7.26(t, J=7.5Hz, IH), 6.90-6.87(m,  (4-Morphin-4hexyl-phenyl) -7.26 (t, J = 7.5 Hz, IH), 6.90-6.87 (m,
우레아 2H), 3.73(m, 4H), 3.01(m, 4H),  Urea 2H), 3.73 (m, 4H), 3.01 (m, 4H),
2.66(s, 3H),  2.66 (s, 3 H),
4-메틸-피페라진 -1ᅳ lW NMR (300 MHz, DMSO, δ ) ： 4-methyl-piperazin -1 eu l W NMR (300 MHz, DMSO , δ):
카르복실산 [2- 9.83(s, IH), 9.22(s, IH), 8.42(s,  Carboxylic acids [2- 9.83 (s, IH), 9.22 (s, IH), 8.42 (s,
104 471 사이클로프로필 -1- IH), 7.95(s, IH), 7.81(s, IH), 7.73- 메틸 -6-(8-메틸- 7.66(m, 2H), 7.25(t, J=7.5Hz, IH), 퀴나졸린 -2-일아미노) - 3.81(s, 3H), 3.47-3.40(m, 4H), 1H-벤즈이미다졸 -4- 2.67(s, 3H), 2.35-2.32(m, 4H), 2.25- 일] -아미드 2.20(m, 4H), 1.03-1.01(m, 4H) 104 471 cyclopropyl-1-IH), 7.95 (s, IH), 7.81 (s, IH), 7.73-methyl-6- (8-methyl-7.66 (m, 2H), 7.25 (t, J = 7.5 Hz , IH), Quinazolin-2-ylamino)-3.81 (s, 3H), 3.47-3.40 (m, 4H), 1H-benzimidazole-4- 2.67 (s, 3H), 2.35-2.32 (m, 4H), 2.25 -Amide] 2.20 (m, 4H), 1.03-1.01 (m, 4H)
¾ NMR (300 MHz, DMSO, δ ) ： ¾ NMR (300 MHz, DMSO, δ) ：
N-[2-이소프로필 -6-(8- 9.85(s, IH), 9.24(s, IH), 8.34(br s, 메틸-퀴나졸린 -2- IH), 8.14(s, IH), 7.97(d, J=8.7Hz,  N- [2-isopropyl-6- (8-9.85 (s, IH), 9.24 (s, IH), 8.34 (br s, methyl-quinazolin-2-IH), 8.14 (s, IH), 7.97 (d, J = 8.7 Hz,
일아미노) -1H- 2H), 7.75 (d, J=8.1Hz, IH), 7.70(d,  Monoamino) -1H-2H), 7.75 (d, J = 8.1 Hz, IH), 7.70 (d,
106 522 벤즈이미다졸 -4-일] -4- J=6.9Hz, IH), 7.30(t, J=7.2Hz, IH),  106 522 benzimidazol-4-yl] -4- J = 6.9 Hz, IH), 7.30 (t, J = 7.2 Hz, IH),
모폴린 -4-일- 7.09(d, J=8.7Hz, 2H) , 3.77(m, 4H) ,  Morpholin-4-yl-7.09 (d, J = 8.7 Hz, 2H), 3.77 (m, 4H),
벤즈아미드 3.26(m, 4H), 2.68(s( 3H), 2.49(m, Benzamide 3.26 (m, 4H), 2.68 (s ( 3H), 2.49 (m,
IH), 1.37(d, J=6.6Hz, IH)  IH), 1.37 (d, J = 6.6 Hz, IH)
¾ NMR (300 MHz, DMS0-d6) 10.20 (s, ¾ NMR (300 MHz, DMS0-d 6 ) 10.20 (s,
N-[2-이소프로필 -6-(8- IH), 9.88 (s, IH), 9.71 (s, IH), 9.23 메틸-퀴나졸린 -2- (d, J=4.2 Hz, IH), 8.33 (d, J=1.5 Hz, 일아미노) -1H- IH), 8.16 (s, IH), 7.90 (s, IH), 7.71  N- [2-isopropyl-6- (8-IH), 9.88 (s, IH), 9.71 (s, IH), 9.23 methyl-quinazolin-2- (d, J = 4.2 Hz, IH), 8.33 (d, J = 1.5 Hz, monoamino) -1H-IH), 8.16 (s, IH), 7.90 (s, IH), 7.71
107 549.4 벤즈이미다졸—4-일] -3- (s, IH), 7.50 (d, J=6.0 Hz, 2H), 7.25  107 549.4 Benzimidazol—4-yl] -3- (s, IH), 7.50 (d, J = 6.0 Hz, 2H), 7.25
(4-메틸-피페라진 -1- (s, IH), 3.55 (s, 2H), 2.68 (s, 3H), 일메틸) -벤즈아미드 2.40 (m, 9H), 2.14 (s, 3H), 1.35 (t,  (4-methyl-piperazine-1- (s, IH), 3.55 (s, 2H), 2.68 (s, 3H), ylmethyl) -benzamide 2.40 (m, 9H), 2.14 (s, 3H), 1.35 (t,
J=6.9 Hz, 6H)  J = 6.9 Hz, 6H)
1-[2-이소프로필 -6-(8- ¾ NMR (300 MHz, DMSO, 6 ) ：  1- [2-isopropyl-6- (8-¾ NMR (300 MHz, DMSO, 6) ：
메틸-퀴나졸린 -2- 12.05(s, IH), 9.70(s, IH), 9.30(s,  Methyl-quinazolin-2-12.05 (s, IH), 9.70 (s, IH), 9.30 (s,
일아미노) -1H- IH), 9.20(s, IH), 8.52(br s, IH) ,  Monoamino) -1H-IH), 9.20 (s, IH), 8.52 (br s, IH),
111 537.1 벤즈이미다졸 -4—일] -3- 8.29(s, IH), 8.08(s, IH), 7.71- (4-모플린 -4-일-페닐) - 7.64(m, 2H), 7.38— 7.35 (m, 2H),  111 537.1 Benzimidazole-4—yl] -3-8.29 (s, IH), 8.08 (s, IH), 7.71- (4-morpholin-4-yl-phenyl) -7.64 (m, 2H), 7.38 — 7.35 (m, 2H),
우레아 7.23(t, J=7.8Hz, IH), 6.89(d, 2H), 3.74-3.71(m, 4H), 3.21-3.12(m, 1H), Urea 7.23 (t, J = 7.8 Hz, IH), 6.89 (d, 2H), 3.74-3.71 (m, 4H), 3.21-3.12 (m, 1H),
3.03—3.01(111， 4H), 2.68(s  3.03—3.01 (111, 4H), 2.68 (s
]H NMR (300 MHz, DMS0-d6) 9.82 (s, ] H NMR (300 MHz, DMS0-d 6 ) 9.82 (s,
N-[2-사이클로프로필- IH), 9.22 (s, IH), 8.27 (brs, IH),  N- [2-cyclopropyl-IH), 9.22 (s, IH), 8.27 (brs, IH),
6-(8ᅳ메틸-퀴나졸린 -2- 8.16 (s, IH), 7.68 (dd, J=17.1, 7.8  6- (8 ᅳ methyl-quinazolin-2-8.16 (s, IH), 7.68 (dd, J = 17.1, 7.8
일아미노) -1H- Hz, 2H), 7.55 (s, IH), 7.38 (m, 2H),  Monoamino) -1H-Hz, 2H), 7.55 (s, IH), 7.38 (m, 2H),
113 533.3 벤즈이미다졸 -4-일 ] -3- 7.24 (t, J=7.5 Hz, IH), 7.16 (d,  113 533.3 benzimidazol-4-yl] -3-7.24 (t, J = 7.5 Hz, IH), 7.16 (d,
(4-메틸-피페라진 -1- J=7.5 Hz, IH), 3.22 (m, 4H), 2.64  (4-Methyl-piperazine-1-J = 7.5 Hz, IH), 3.22 (m, 4H), 2.64
일) -벤즈아미드 (s, 3H), 2.49 (m, 4H), 2.22 (s, 3H),  I) -benzamide (s, 3H), 2.49 (m, 4H), 2.22 (s, 3H),
2.12 m, IH), 1.01 (d, J=7.2 Hz, 4H)  2.12 m, IH), 1.01 (d, J = 7.2 Hz, 4H)
¾ 醒 R (300 MHz, DMSO, δ ) ：  ¾ 醒 R (300 MHz, DMSO, δ) ：
1-[2ᅳ사이클로프로필- 9.81(s, IH), 9.28-9.22(m, 2H), 8.43- 1-메틸— 6-(8-메틸- 8.35(m, 2H), 8.19(s, IH), 7.73- 퀴나졸린 -2-일아미노) - 7.66(m, 2H), 7.36(m, 2H), 7.25(t,  1- [2 ᅳ cyclopropyl-9.81 (s, IH), 9.28-9.22 (m, 2H), 8.43- 1-methyl- 6- (8-methyl-8.35 (m, 2H), 8.19 (s, IH) , 7.73-quinazolin-2-ylamino) -7.66 (m, 2H), 7.36 (m, 2H), 7.25 (t,
114 549.1 1H-벤즈이미다졸 -4- J=7.2Hz, IH), 6.89(m, 2H), 3.82(s,  114 549.1 1H-benzimidazole-4-J = 7.2 Hz, IH), 6.89 (m, 2H), 3.82 (s,
일] -3-(4-모폴린 -4-일- 3H), 3.73-3.70(m, 4H), 3.03-2, 99 Cm,  General] -3- (4-morpholin-4-yl-3H), 3.73-3.70 (m, 4H), 3.03-2, 99 Cm,
페닐) -우레아 4H), 2.68(s, 3H), 2.24(m, IH),  Phenyl) -urea 4H), 2.68 (s, 3H), 2.24 (m, IH),
1.05(d, 4H)  1.05 (d, 4 H)
모폴린 -4-카르복실산 ¾ NMR (300 MHz, DMSO, δ ) ：  Morpholine-4-carboxylic acid ¾ NMR (300 MHz, DMSO, δ) ：
[1，2-다이메틸-6—(8- 9.86(s, IH), 9.24(s, IH), 8.54(s, ' [1,2-dimethyl-6— (8-9.86 (s, IH), 9.24 (s, IH), 8.54 (s, '
메틸-퀴나졸린 -2- IH), 8.16(s, IH), 7.86(s, IH), 7.75- Methyl-quinazolin-2-IH), 8.16 (s, IH), 7.86 (s, IH), 7.75-
123 432.3 일아미노) -1H- 7.67(ra, 2H), 7.25(t, J=7.2Hz, IH), 123 432.3 monoamino) -1H-7.67 (ra, 2H), 7.25 (t, J = 7.2 Hz, IH),
벤즈이미다졸 -4—일] - 3.87(s, 3H), 3.65-3.62(m, 4H),  Benzimidazole-4—yl]-3.87 (s, 3H), 3.65-3.62 (m, 4H),
아미드 3.47(m, 4H), 2.67(s, 3H), 2.49(s, 3H) 66 Amide 3.47 (m, 4H), 2.67 (s, 3H), 2.49 (s, 3H) 66
Figure imgf000100_0001
Figure imgf000100_0001
^6ΐ.00/ΐΐΟΖΗΜΧ3Λ 060 0/ZT0Z OAV 001 ^ 6ΐ.00 / ΐΐΟΖΗΜΧ3Λ 060 0 / ZT0Z OAV 001
Figure imgf000101_0001
Figure imgf000101_0001
1?6ΐ.00/110ΖΗΜ/Χ3<Ι 060»0/Π0Ζ OAV 메틸-퀴나졸린 -2- 7.66(m, 2H), 7.25(t, J=7.5Hz, IH), 1? 6ΐ.00 / 110ΖΗΜ / Χ3 <Ι 060 »0 / Π0Ζ OAV Methyl-quinazolin-2- 7.66 (m, 2H), 7.25 (t, J = 7.5 Hz, IH),
일아미노) -1H- ' 3.70(s, 3H), 3.48-3.30(m, 4H),  Monoamino) -1H- '3.70 (s, 3H), 3.48-3.30 (m, 4H),
벤즈이미다졸 -4-일] - 2.67(s, 3H), 2.51-2.38(m, 8H) ,  Benzimidazol-4-yl] -2.67 (s, 3H), 2.51-2.38 (m, 8H),
아미드 0.99(d, 6H)  Amide 0.99 (d, 6H)
¾賺 (300 MHz, DMSO, δ ) ：  ¾ 賺 (300 MHz, DMSO, δ) ：
^[1-에틸-2—메틸-6ᅳ 9.99(s, IH), 9.73(s, IH), 9.25(s,  ^ [1-ethyl-2—methyl-6 ᅳ 9.99 (s, IH), 9.73 (s, IH), 9.25 (s,
(8-메틸ᅳ퀴나졸린 -2- IH), 8.69(s, IH), 8.15(br s, IH) ,  (8-methylkequinazolin-2-IH), 8.69 (s, IH), 8.15 (br s, IH),
일아미노) -1H- 7.99-7.96(iii, 2H)， 7.75-7.67(m, 2H),  Monoamino) -1H-7.99-7.96 (iii, 2H), 7.75-7.67 (m, 2H),
133 536.5 벤즈이미다졸 -4-일] -4- 7.49-7.45(m( 2H)， 7.27(t, J=7.2Hz( 133 536.5 benzimidazol-4-yl] -4- 7.49-7.45 (m ( 2H), 7.27 (t, J = 7.2 Hz (
모폴린 -4-일메틸- IH), 4.22(m, 2H), 3.60-3.51(m, 6H),  Morpholin-4-ylmethyl-IH), 4.22 (m, 2H), 3.60-3.51 (m, 6H),
벤즈아미드 2.68(s, 3H), 2.54(s, 3H), 2.39- 2.33(m, 4H), 1.38(t,  Benzamide 2.68 (s, 3H), 2.54 (s, 3H), 2.39-2.33 (m, 4H), 1.38 (t,
¾ NMR (300 MHz, DMSO, δ ) ：  ¾ NMR (300 MHz, DMSO, δ) ：
4-메틸-피페라진 -1- 9.81(s, IH), 9.21(s, IH) , 8.51(s,  4-Methyl-piperazine-1- 9.81 (s, IH), 9.21 (s, IH), 8.51 (s,
카르복실산 [1-에틸-2- IH), 8.16(s, IH), 7.79(s, IH), 7.73- 메틸 -6-(8—메틸- 7.65(m, 2H), 7.25(t, J=7.2Hz, IH),  Carboxylic Acid [1-Ethyl-2-IH), 8.16 (s, IH), 7.79 (s, IH), 7.73-Methyl-6- (8—Methyl-7.65 (m, 2H), 7.25 (t, J = 7.2 Hz, IH),
134 459.3 퀴나졸린 -2-일아미노) - 4.18(q, J=7.5Hz, 2H), 3.55(m, 4H),  134 459.3 Quinazolin-2-ylamino)-4.18 (q, J = 7.5 Hz, 2H), 3.55 (m, 4H),
1H-벤즈이미다졸 -4- 2.66(s, 3H), 2.60-2.58 m, 4H),  1H-benzimidazole-4- 2.66 (s, 3H), 2.60-2.58 m, 4H),
일]—아미드 2.53(s, 3H), 2.36(s, 3H), 1.36(t,  General] —amide 2.53 (s, 3H), 2.36 (s, 3H), 1.36 (t,
J=7.2Hz, 3H)  J = 7.2Hz, 3H)
모폴린 -4-카르복실산 ¾ NMR (300 MHz, DMS으 d6) 9.85 (s, Morpholine-4-carboxylic acid ¾ NMR (300 MHz, d 6 with DMS) 9.85 (s,
[2-사이클로프로필一 1- IH), 9.22 (s, IH), 8.54 (s, IH),  [2-cyclopropyll 1-IH), 9.22 (s, IH), 8.54 (s, IH),
에틸 -6-(8ᅳ메틸- 8.00 (s, IH), 7.75 (s, IH), 7.70 (dd,  Ethyl-6- (8 ᅳ methyl-8.00 (s, IH), 7.75 (s, IH), 7.70 (dd,
135 472.3 퀴나졸린 -2-일아미노) - J=14.7, 7.2 Hz, 2H), 7.25 (t, J=7.8  135 472.3 Quinazolin-2-ylamino) -J = 14.7, 7.2 Hz, 2H), 7.25 (t, J = 7.8
1H-벤즈이미다졸 -4- Hz, IH), 4.30 (m, 2H), 3.63 (t, J=3.9 일] -아미드 Hz, 4H), 3.43 (t, J=4.5 Hz, 4H), 2.67 (s, 3H), 2.22 (m, 1H), 1.40 (t, J=6.9 Hz, 3H), 1.02 (d, J=6.0 Hz, 4H) 1H-benzimidazole-4-Hz, IH), 4.30 (m, 2H), 3.63 (t, J = 3.9 day] -amide Hz, 4H), 3.43 (t, J = 4.5 Hz, 4H), 2.67 (s, 3H), 2.22 (m, 1H), 1.40 (t, J = 6.9 Hz, 3H), 1.02 (d, J = 6.0 Hz, 4H)
¾ NMR (300 MHz, DMS0-ds) 9.83 (s,¾ NMR (300 MHz, DMS0-d s ) 9.83 (s,
4-메틸-피페라진 -1- 1H), 9.22 (s, 1H), 8.52 (s, 1H), 카르복실산 [2- 8.17 (s, 1H), 7.94 (s, 1H), 7.74 (d 사이클로프로필ᅳ 1- J=4 .5 Hz ， W, , 7.68 (dd, J=15.0, 6.3 에틸 -6-(8-메틸- Hz, 2H), 7 .25 (t, J=7.2 Hz, 1H), 4.32 퀴나졸린 -2-일아미노) - (m, 2H), 3 .45 (t, J =4.5 Hz, 4H), 2.67 1H-벤즈이미다졸 -4- (s, 3H), 2 .34 (t, J=4.8 Hz, 4H), 2.24 일]—아미드 (m, 1H), 2 .20 (s, 3H), 1.40 (t, J=7.2 4-Methyl-piperazine-1- 1H), 9.22 (s, 1H), 8.52 (s, 1H), carboxylic acids [2- 8.17 (s, 1H), 7.94 (s, 1H), 7.74 (d cyclo Propyl ᅳ 1- J = 4.5 Hz, W,, 7.68 (dd, J = 15.0, 6.3 ethyl-6- (8-methyl-Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H) , 4.32 quinazolin-2-ylamino)-(m, 2H), 3.45 (t, J = 4.5 Hz, 4H), 2.67 1H-benzimidazole-4- (s, 3H), 2.34 ( t, J = 4.8 Hz, 4H), 2.24 days] —amide (m, 1H), 2.20 (s, 3H), 1.40 (t, J = 7.2
Hz, 3H), 1 .03 (d, J=6.6 Hz, 4H) Hz, 3H), 1.03 (d, J = 6.6 Hz, 4H)
¾匪 R (300 MHz, DMS0-ds) 9.84 (s,¾ 匪 R (300 MHz, DMS0-d s ) 9.84 (s,
4-이소프로필- 1H), 9.22 (s, 1H), 8.52 (s, 1H), 피페라진 -1-카르복실산 4-isopropyl-1H), 9.22 (s, 1H), 8.52 (s, 1H), piperazine-1-carboxylic acid
8.20 (s, 1H), 7.91 (s, 1H), 7.75 (s, 8.20 (s, 1 H), 7.91 (s, 1 H), 7.75 (s,
[2-사이클로프로필 -1ᅳ [2-cyclopropyl -1 ᅳ
1H), 7.70 (dd, J=15.3, 7.5 Hz, 2H) , I에틸— 6-(8-메틸- 7.25 (t, J=7.2 Hz, 1H), 4.32 (m, 2H), 퀴나졸린 -2-일아미노) - 3.43 (m, 4H), 2.67 (s, 3H), 2.22 (m, 1H-벤즈이미다졸 -4- 1H), 1.40 (t, J=7.2 Hz, 3H), 1.20 (d, 일]—아미드  1H), 7.70 (dd, J = 15.3, 7.5 Hz, 2H), Iethyl— 6- (8-methyl-7.25 (t, J = 7.2 Hz, 1H), 4.32 (m, 2H), quinazoline-2 -Ylamino) -3.43 (m, 4H), 2.67 (s, 3H), 2.22 (m, 1H-benzimidazole-4-1H), 1.40 (t, J = 7.2 Hz, 3H), 1.20 (d, General] —amide
J=6.0 Hz, 4H), 0.98 (d, J=6.3 Hz, 6H) 테트라하이드로-피란ᅳ ¾ NMR (300 MHz, DMS0-d6) 9.85 (s, 4-카르복실산 [2- 1H), 9.39 (s, 1H), 9.22 (s, 1H), 사이클로프로필 -1- 8.54 (s, 1H)( 8.12 (s, 1H), 7.70 (dd I에틸 -6— (8-메틸- J=15.0, 8.1 Hz, 2H), 7.25 (t, J=6.9 퀴나졸린 -2-일아미노) - Hz, 1H), 4.32 (m, 2H), 3.89 (t, 1H-벤즈이미다졸 -4- J=10.8 Hz, 4H), 3.15 (m, 1H), 2.90 일]一아미드 On, 1H), 2.66 (s, 3H), 2.22 (m, 1H), εοτ J = 6.0 Hz, 4H), 0.98 (d, J = 6.3 Hz, 6H) tetrahydro-pyranium ¾ NMR (300 MHz, DMS0-d 6 ) 9.85 (s, 4-carboxylic acid [2- 1H), 9.39 (s, 1H), 9.22 (s, 1H), cyclopropyl-1-8.54 (s, 1H) ( 8.12 (s, 1H), 7.70 (dd Iethyl-6— (8-methyl-J = 15.0, 8.1 Hz, 2H), 7.25 (t, J = 6.9 quinazolin-2-ylamino) -Hz, 1H), 4.32 (m, 2H), 3.89 (t, 1H-benzimidazole-4-J = 10.8 Hz , 4H), 3.15 (m, 1H), 2.90 days] 一 amide On, 1H), 2.66 (s, 3H), 2.22 (m, 1H), εοτ
Figure imgf000104_0001
Figure imgf000104_0001
teiLOO/UOZ ^l/LDd 0601"1"0/ΖΪ0Ζ OAV J=7.2 Hz, 3H), 1.08 (d, J=8.4 Hz, 4H) teiLOO / UOZ ^ l / LDd 0601 "1" 0 / ΖΪ0Ζ OAV J = 7.2 Hz, 3H), 1.08 (d, J = 8.4 Hz, 4H)
Ή NMR (300 MHz, DMS0-d6) 9.94 (s, MR NMR (300 MHz, DMS0-d 6 ) 9.94 (s,
IH), 9.65 (s, IH), 9.23 (s, IH),  IH), 9.65 (s, IH), 9.23 (s, IH),
N-[2-사이클로프로필- 8.58 (d, J=1.8 Hz, IH)， 8.23 (d,  N- [2-cyclopropyl-8.58 (d, J = 1.8 Hz, IH), 8.23 (d,
1-에틸ᅳ6-(8-메틸- J=1.8 Hz, IH), 8.19 (s, IH), 7.70 1-ethyl ᅳ 6- (8-methyl-J = 1.8 Hz, IH), 8.19 (s, IH), 7.70
퀴나졸린 -2-일아미노) - (dd, J=15.0, 8.1 Hz, 2H), 7.26 (t, 444.3 1H-벤즈이미다졸 -4- J=7.8 Hz, IH), 4.33 (m, 2H), 3.12 (s, 일] -2-다이메틸아미노- 2H), 2.67 (s, 3H), 2.33 (s, 6H)， Quinazolin-2-ylamino)-(dd, J = 15.0, 8.1 Hz, 2H), 7.26 (t, 444.3 1H-benzimidazole-4-J = 7.8 Hz, IH), 4.33 (m, 2H), 3.12 (s, day) -2-dimethylamino-2H), 2.67 (s, 3H), 2.33 (s, 6H),
아세트아미드 Acetamide
2.25 (m, IH), 1.41 (d, J=7.2 Hz, 3H),  2.25 (m, IH), 1.41 (d, J = 7.2 Hz, 3H),
1.04 (d, J=8.7 Hz, 4H)  1.04 (d, J = 8.7 Hz, 4H)
¾ NMR (300 MHz, DMS0-ds) 9.84 (s, ¾ NMR (300 MHz, DMS0-d s ) 9.84 (s,
2 ,6-다이메틸 -모폴린- IH), 9.22 (s, IH), 8.54 (d, J=1.5 Hz,  2,6-dimethyl-morpholine- IH), 9.22 (s, IH), 8.54 (d, J = 1.5 Hz,
4-카르복실산 [2- IH), 8.02 (s, IH), 7.68 (m, 3H), 7.25 사이클로프로필 -1- (t, J=7.5 Hz, IH), 4.33 Cm, 2H), 3.97 에틸 -6-(8-메틸- 500.3 4-carboxylic acid [2-IH), 8.02 (s, IH), 7.68 (m, 3H), 7.25 cyclopropyl-1- (t, J = 7.5 Hz, IH), 4.33 Cm, 2H), 3.97 ethyl -6- (8-methyl-500.3
(d, J=11.4 Hz, 2H), 3.54 (m, 2H) ,  (d, J = 11.4 Hz, 2H), 3.54 (m, 2H),
퀴나졸린 -2-일아미노) - 2.67 (s, 3H), 2.21 (m, IH), 1.40 (t, Quinazolin-2-ylamino)-2.67 (s, 3H), 2.21 (m, IH), 1.40 (t,
1H-벤즈이미다졸 -4- J=6.9 Hz, 3H), 1.12 (d, J=6.3 Hz, 1H-benzimidazole-4-J = 6.9 Hz, 3H), 1.12 (d, J = 6.3 Hz,
일] -아미드 General] -amide
6H), 1.03 (d, J=6.6 Hz, 4H)  6H), 1.03 (d, J = 6.6 Hz, 4H)
4-이소프로필- ]H NMR (300 MHz, DMSO, δ ) ： 4-isopropyl- ] H NMR (300 MHz, DMSO, δ) ：
피페라진 -1-카르복실산 9.85(s, IH), 9.22(s, IH) , 8.53(s, Piperazine-1-carboxylic acid 9.85 (s, IH), 9.22 (s, IH), 8.53 (s,
[1-에틸 -2-메틸 -6-(8- IH), 8.14(s, IH), 7.77(s, IH), 7.76- 메틸-퀴나졸린 _2ᅳ 7.66(iii, 2H), 7.25(d, J=7.5Hz, IH) , 487.3 일아미노) -1H- 4.19(q, 2H), 3.50(m, 4H) , 3.33(m,  [1-ethyl-2-methyl-6- (8-IH), 8.14 (s, IH), 7.77 (s, IH), 7.76-methyl-quinazolin _2 '7.66 (iii, 2H), 7.25 (d, J = 7.5 Hz, IH), 487.3 ylamino) -1H-4.19 (q, 2H), 3.50 (m, 4H), 3.33 (m,
벤즈이미다졸 -4-일] - IH), 2.66(s, 3H), 2.59-2.47(m, 7H), Benzimidazol-4-yl] -IH), 2.66 (s, 3H), 2.59-2.47 (m, 7H),
아미드 1.36(t, J=7.2Hz, 3H), 1.02(d, 6H) 901 Amide 1.36 (t, J = 7.2 Hz, 3H), 1.02 (d, 6H) 901
Figure imgf000106_0001
Figure imgf000106_0001
K oo/nozaM/i d OAV 901 K oo / nozaM / id OAV 901
Figure imgf000107_0001
Figure imgf000107_0001
^6ΐ.00/ΐΙΟΖΗΜ/Χ3«Ι 060 0/ZT0Z OAV ^ 6ΐ.00 / ΐΙΟΖΗΜ / Χ3 «Ι 060 0 / ZT0Z OAV
Figure imgf000108_0001
Figure imgf000108_0001
060»0/ZI0Z OAV IH-벤즈이미다졸 -4- (s, 3H), 3.15 (s, 4H), 3.03 (m, 4H), 일]—아미드 2.63 (s, 3H), 2.46 (s, 3H), 1.96 (s, 060 »0 / ZI0Z OAV IH-benzimidazole-4- (s, 3H), 3.15 (s, 4H), 3.03 (m, 4H), day] —amide 2.63 (s, 3H), 2.46 (s, 3H), 1.96 (s,
3H)  3H)
¾ NMR (300 MHz, DMSO, δ ) ： ¾ NMR (300 MHz, DMSO, δ) ：
2， 6-다이메틸 -모폴린- 9.83(s, IH), 9.22(s, IH), 8.17- 4-카르복실산 [2- 8.13(m, 2H), 7.73-7.65(m, 2H),  2, 6-dimethyl-morpholine-9.83 (s, IH), 9.22 (s, IH), 8.17-4 carboxylic acid [2-8.13 (m, 2H), 7.73-7.65 (m, 2H),
사이클로프로필 -6-(8- 7.41(br s, IH), 7.25(t, J=7.2Hz, IH), 메틸-퀴나졸린 -2- 486.2 Cyclopropyl-6- (8-7.41 (br s, IH), 7.25 (t, J = 7.2 Hz, IH), methyl-quinazolin-2-486.2
3.53-3.37(ni, 4H), 3.18(s, 3H),  3.53-3.37 (ni, 4H), 3.18 (s, 3H),
일아미노)— 1H- 2.63(s, 3H), 2.41(m, IH), 2.20- 벤즈이미다졸 -4-일 ] - 2.08(m, 2H), 1.03(d, J=6.0Hz, 6H), Monoamino) — 1H-2.63 (s, 3H), 2.41 (m, IH), 2.20- benzimidazol-4-yl] -2.08 (m, 2H), 1.03 (d, J = 6.0 Hz, 6H),
메틸-아미드 Methyl-amide
0.79(d, J=6.3Hz, 4H)  0.79 (d, J = 6.3 Hz, 4H)
¾匪 R (300 MHz, DMS0-ds) 12.20 (s, ¾ 匪 R (300 MHz, DMS0-d s ) 12.20 (s,
2 ,6-다이메틸 -모폴린- IH), 9.86 (s, IH), 9.27 (s, IH), 8.27  2,6-dimethyl-morpholine- IH), 9.86 (s, IH), 9.27 (s, IH), 8.27
4-카르복실산 메틸 -[2- (s, IH), 7.70 (dd, J=14.4, 7.8 Hz, 4-carboxylic acid methyl-[2- (s, IH), 7.70 (dd, J = 14.4, 7.8 Hz,
메틸 -6— (8-메틸- 2H), 7.39 (s, IH), 7.25 (t, J=7.5 Hz, 460.3 퀴나졸린 -2-일아미노) - IH), 3.19 (m, 4H), 3.15 (s, 3H), 2.63 Methyl-6- (8-methyl-2H), 7.39 (s, ih), 7.25 (t, J = 7.5 Hz, 460.3 quinazolin-2-ylamino) -IH), 3.19 (m, 4H), 3.15 ( s, 3 H), 2.63
1H—벤즈이미다졸 -4- (s, 3H)( 2.40 (s, 3H), 2.20 (m, 3H), 일]—아미드 1H—benzimidazole-4- (s, 3H) ( 2.40 (s, 3H), 2.20 (m, 3H), day] —amide
0.79 (d, J=5.7 Hz, 6H)  0.79 (d, J = 5.7 Hz, 6H)
테트라하이드로-피란- ¾ NMR (300 MHz, DMS0-d6) 12.28 (s, Tetrahydro-pyran- ¾ NMR (300 MHz, DMS0-d 6 ) 12.28 (s,
4-카르복실산 [2- IH), 9.92 (sᅳ IH), 9.24 (s, IH), 8.32 사이클로프로필— 6-(8- (s, IH), 7.69 (m, 2H), 7.26 (t, J=7.2 메틸 -퀴나졸린一 2- Hz, IH), 3.68 (d, J=9.3 Hz, 2H), 457.3 일아미노) -1H- 3.20 (s, 4H)( 2.90 (m, 2H)， 2.63 (s, 벤즈이미다졸 -4-일] - 3H), 2.09 (m, IH), 1.60 (m, 2H), 1.47 메틸ᅭ아미드 (m, 2H), 1.03 (d, J=8.1 Hz, 4H) ¾ NMR (300 MHz, DMS0, δ ) ： l-(3-플루오로ᅳ 5- 9.82(sᅳ IH), 9.47(s, IH), 9.22(s, 4-carboxylic acid [2-IH), 9.92 (s ᅳ IH), 9.24 (s, IH), 8.32 cyclopropyl— 6- (8- (s, IH), 7.69 (m, 2H), 7.26 (t , J = 7.2 methyl-quinazolin1 2- Hz, IH), 3.68 (d, J = 9.3 Hz, 2H), 457.3 monoamino) -1H-3.20 (s, 4H) ( 2.90 (m, 2H), 2.63 (s, benzimidazol -4-] - 3H), 2.09 ( m, IH), 1.60 (m, 2H), 1.47 yo-methyl-amide (m, 2H), 1.03 ( d, J = 8.1 Hz, 4H) ¾ NMR (300 MHz, DMS0, δ): l- (3-fluoro ᅳ 5-9.82 (s ᅳ IH), 9.47 (s, IH), 9.22 (s,
모폴린—4-일-페닐) -3- IH), 8.79(s, IH), 8.20(s, IH),  Morpholine—4-yl-phenyl) -3-IH), 8.79 (s, IH), 8.20 (s, IH),
[2-메틸— 6-(8—메틸- [2-methyl- 6- (8—methyl-
178 8.11(s, IH), 7.73-7.65(m, 2H), 527.1 퀴나졸린 -2-일아미노) - 7.25(t, J=7.5Hz, IH), 6.85-6.83(m, 178 8.11 (s, IH), 7.73-7.65 (m, 2H), 527.1 quinazolin-2-ylamino)-7.25 (t, J = 7.5 Hz, IH), 6.85-6.83 (m,
1H-벤즈이미다졸 -4- 2H), 6 ·42-6.38(πι, IH), 3.72(m, 4H) ,  1H-benzimidazole-4-2H), 42.42-6.38 (πι, IH), 3.72 (m, 4H),
일] -우레아  Day] -urea
3.10(m, 4H), 2.67(s, 3H), 2.54(s, 3H)  3.10 (m, 4H), 2.67 (s, 3H), 2.54 (s, 3H)
N-[2-사이클로프로필- ¾ NMR (300 MHz, DMSO, δ ) ：  N- [2-cyclopropyl-¾ NMR (300 MHz, DMSO, δ) ：
6-(8-메틸-퀴나졸린 -2- 9.82(s, IH), 9.22(s, IH), 8.27(sᅳ  6- (8-methyl-quinazolin-2- 9.82 (s, IH), 9.22 (s, IH), 8.27 (s
일아미노) -1H- IH), 7.72-7.64(m, 2H), 7.56(s, IH),  Monoamino) -1H-IH), 7.72-7.64 (m, 2H), 7.56 (s, IH),
179 520.1 벤즈이미다졸 -4-일] -3- 7.43-7.36(m, 2H) , 7.26-7.16(m, 2H),  179 520.1 benzimidazol-4-yl] -3- 7.43-7.36 (m, 2H), 7.26-7.16 (m, 2H),
모폴린 _4一일一 3.78-3.69(m, 4H), 3.21-3.18 (m, 4H), Morpholine _ 4 one day 3.78-3.69 (m, 4H), 3.21-3.18 (m, 4H),
벤즈아미드 2.64(s, 3H), 2.12(m, IH), 1.02(m, 4H)  Benzamide 2.64 (s, 3H), 2.12 (m, IH), 1.02 (m, 4H)
¾匪 R (300 MHz, DMSO, δ ) ：  ¾ 匪 R (300 MHz, DMSO, δ) ：
N-[2-메틸 -6-(8-메틸- 9.84(s, IH), 9.22(s, IH), 8.38(s,  N- [2-methyl-6- (8-methyl-9.84 (s, IH), 9.22 (s, IH), 8.38 (s,
퀴나졸린 -2-일아미노) - IH), 8.12(s, IH), 7.73-7.67(m, 2H),  Quinazolin-2-ylamino) -IH), 8.12 (s, IH), 7.73-7.67 (m, 2H),
180 1H-벤즈이미다졸 -4- 494.5  180 1H-benzimidazole-4-494.5
7.56(s, IH), 7.46-7.36(m, 2H), 7.27— 일] -3-모폴린 -4-일- 7.16(m, 3H), 3.77(m, 4H), 3.20(m,  7.56 (s, IH), 7.46-7.36 (m, 2H), 7.27—Japanese] -3-morpholin-4-yl- 7.16 (m, 3H), 3.77 (m, 4H), 3.20 (m,
벤즈아미드  Benzamide
4H), 2.65(s, 3H), 2.55(s, 3H)  4H), 2.65 (s, 3H), 2.55 (s, 3H)
¾ NMR (300 MHz, DMSO, δ ) ：  ¾ NMR (300 MHz, DMSO, δ) ：
1-[2-사이클로프로필- 12.08(s, IH), 9.76(s, IH), 9.56(br s,  1- [2-cyclopropyl-12.08 (s, IH), 9.76 (s, IH), 9.56 (br s,
6-(8-메틸-퀴나졸린 -2- IH), 9.21(s, IH), 8.62(s, IH),  6- (8-methyl-quinazolin-2-ih), 9.21 (s, ih), 8.62 (s, ih),
일아미노) -1H- Monoamino) -1H-
183 8.27(br s, IH) , 8.09(s, IH), 7.72- 553.1 벤즈이미다졸 -4-일] -3- 7.64(m, 2H), 7.24(t, J=7.2Hz, IH), 183 8.27 (br s, IH), 8.09 (s, IH), 7.72-553.1 benzimidazol-4-yl] -3- 7.64 (m, 2H), 7.24 (t, J = 7.2 Hz, IH),
(3-플루오로 -5-모폴린- 6.87-6..82(m, 2H), 6.42-6.38(ra, IH),  (3-fluoro-5-morpholine-6.87-6..82 (m, 2H), 6.42-6.38 (ra, IH),
4-일—페닐) -우레아  4-yl—phenyl) -urea
3.72(m, 4H), 3.10(m, 4H), 2.67(s, 3H), 2.17— 2.13 (m, 1 3.72 (m, 4H), 3.10 (m, 4H), 2.67 (s, 3H), 2.17— 2.13 (m, 1
모폴린 -4-카르복실산 ]H NMR (300 MHz, DMSO, δ ) ： Morpholine-4-carboxylic acid ] H NMR (300 MHz, DMSO, δ) ：
[2-사이클로프로필 -6- lO.OKs, 1H), 8.72(d, J=4.8Hz, 1H),  (2-cyclopropyl-6-lO.OKs, 1H), 8.72 (d, J = 4.8 Hz, 1H),
(4-트리플루오로메틸- 8.25(br s, 1H), 8.13(br s, 1H), (4-trifluoromethyl-8.25 (br s, 1H), 8.13 (br s, 1H),
184 448.3 피리미딘 -2-일아미노) - 7.66(s, 1H), 7.47(br s, 1H), 7.14(d, 184 448.3 pyrimidin-2-ylamino) -7.66 (s, 1H), 7.47 (br s, 1H), 7.14 (d,
1H-벤즈이미다졸ᅳ 4- J=4.8Hz, 1H), 3.64-3.61(m, 4H), 3.45- 일] -아미드 3.42(m, 4H), 2.11(m, 1H), 1.01(m, 4H)  1H-benzimidazolazole 4- J = 4.8Hz, 1H), 3.64-3.61 (m, 4H), 3.45-yl] -amide 3.42 (m, 4H), 2.11 (m, 1H), 1.01 (m, 4H )
실시예 V: 벤즈이미다졸유도체 -(2) Example V Benzimidazole Derivatives-(2)
벤즈이미다졸의 유도체 중 2번 위치로의 치환기 도입은 다음과 같은 반응을 이용하였다. 합성방법은 문헌 [Studii si Cercetari Stiintifice: Chimie si Inginer ie Chimica, Biotehnologi i , Industrie Al imentara (Universitatea Bacau) , 8(1)， 19-28； 2007, Asian Journal of Chemistry, 21(7), 5207-5211； 2009] 및 PCT 출원번호 겨2009/090548호에 기재된 합성 방법을 이용하였다. The introduction of a substituent to position 2 in the derivative of benzimidazole was performed using the following reaction. Synthesis methods are described in Studii si Cercetari Stiintifice: Chimie si Inginer ie Chimica, Biotehnologi i, Industrie Al imentara (Universitatea Bacau), 8 (1), 19-28; 2007, Asian Journal of Chemistry, 21 (7), 5207- 5211; 2009 and the synthesis method described in PCT Application No. 2009/090548.
Figure imgf000111_0001
Figure imgf000111_0001
상기 실시예 V에서 제조한 벤즈이미다졸 화합물 및 각각 상응하는 출발물질을 이용하여 실시예 IV과 동일한 방식으로 수행하여 하기 표 5에 기재된 실시예의 화합물을 제조하였다. [표 5] Using the benzimidazole compound prepared in Example V and the corresponding starting materials, respectively, the preparation was carried out in the same manner as in Example IV, to prepare the compounds of the examples shown in Table 5 below. TABLE 5
Figure imgf000112_0001
(8-메틸-퀴나졸린 -2- 1H), 4.83 (s, 2H), 4.18 (t, J=6.3 Hz, 일) -아민 2H), 2.68 (s, 3H), 2.52 (s, 3H), 2.26
Figure imgf000112_0001
(8-methyl-quinazolin-2-1H), 4.83 (s, 2H), 4.18 (t, J = 6.3 Hz, one) -amine 2H), 2.68 (s, 3H), 2.52 (s, 3H), 2.26
(m, 6H), 1.93 (m, 2H), 1.38 (m, 4H),  (m, 6H), 1.93 (m, 2H), 1.38 (m, 4H),
1.25 (m, 2H)  1.25 (m, 2H)
피페라진 -1-일 -[2-(2- ¾ NMR (300 MHz, DMSO, δ ) ： Piperazin-1-yl-[2- (2-¾ NMR (300 MHz, DMSO, δ) ：
트리플루오로메틸 -3H- 10.16(s, IH), 9.35(s, IH)， 8.70(s, 벤즈이미다졸 -5- IH), 8.22(br s, lH),7.98(d, J=8.1Hz, Trifluoromethyl-3H-10.16 (s, IH), 9.35 (s, IH), 8.70 (s, benzimidazole-5-IH), 8.22 (br s, lH), 7.98 (d, J = 8.1 Hz ,
442.1 일아미노) -퀴나졸린 -그 IH), 7.73— 7.64(m, 2H), 7.59(s, IH), 일] -메탄온 7.34(d, J=8.1Hz, IH), 3.36(m, 4H) ,  442.1 monoamino) -quinazolin-IH), 7.73— 7.64 (m, 2H), 7.59 (s, IH), general] -methanone 7.34 (d, J = 8.1 Hz, IH), 3.36 (m, 4H ),
2.83-2.74(m, 4H)  2.83-2.74 (m, 4H)
2-(2-사이클로프로필- ¾圏 R (300 MHz, CD30Ds, δ ) ： 2- (2-cyclopropyl-¾- R (300 MHz, CD 3 0D s , δ) ：
3H-벤즈이미다졸 -5- 9.14(d, J=0.9Hz, IH), 8.51(s, IH), 일아미노) -퀴나졸린 -7- 8.19(s, IH), 7.81(m, 2H) , 7.38(m, 360 카르복실산 메틸 2H), 3.94(s, 3H), 1.19(m, IH) , 1.23- 에스터 1 ·14(ηι, 4H) 3H-benzimidazole-5.14 (d, J = 0.9 Hz, IH), 8.51 (s, IH), monoamino) -quinazolin-7-8.19 (s, IH), 7.81 (m, 2H), 7.38 (m, 360 methyl carboxylic acid 2H), 3.94 (s, 3H), 1.19 (m, IH), 1.23-ester 1-14 (ηι, 4H)
]H NMR (300 MHz, DMSO, δ ) ： ] H NMR (300 MHz, DMSO, δ) ：
(4-메틸-피페라진 -1- 10.16(s, IH), 9.36(s, IH), 8.70(s, 일) -[2— (2- IH), 8.14(s, IH), 7.98(d, J=8.1Hz, 트리플루오로메틸 -3H- IH), 7.73-7.64(m, 2H), 7.57(s, IH) , 456.2 벤즈이미다졸 -5- 7.32(d, J=8.1Hz, IH), 3.66(m, 2H), 일아미노) -퀴나졸린 -7- 3.33(m, 2H), 2.40(m, 2H) , 2.28(m,  (4-Methyl-piperazine-1- 10.16 (s, IH), 9.36 (s, IH), 8.70 (s, day)-[2— (2-IH), 8.14 (s, IH), 7.98 (d , J = 8.1 Hz, trifluoromethyl-3H-IH), 7.73-7.64 (m, 2H), 7.57 (s, IH), 456.2 benzimidazole-5-7.32 (d, J = 8.1 Hz, IH) , 3.66 (m, 2H), monoamino) -quinazoline-7-3.33 (m, 2H), 2.40 (m, 2H), 2.28 (m,
일] -메탄은 General]-Methane
2H), 2.20(s, IH)  2H), 2.20 (s, IH)
2-(2-사이클로프로필- ¾ NMR (300 MHz, CD30D, δ ) ： 2- (2-cyclopropyl-¾ NMR (300 MHz, CD 3 0D, δ) ：
3H-벤즈이미다졸 -5- 9.22(s, IH), 8.45(d, J=1.5Hz, IH) , 3H-benzimidazole-5-9.22 (s, IH), 8.45 (d, J = 1.5 Hz, IH),
478 일아미노) -퀴나졸린 - 8.21(br s, 2H), 8.12(s, IH), 7.94(d,  478 ylamino) -quinazolin-8.21 (br s, 2H), 8.12 (s, IH), 7.94 (d,
7-카르복실산 (2- J=8.4 Hz, IH), 7.74(d, J=6.6 Hz, IH), 모폴린 -4-일-에틸) - 7.55(m, 2H), 3.79(m, 4H), 3.67(t, 아미드 J=6.6Hz, 2H), 2.91(t, J=6.6Hz, 2H), 7-carboxylic acid (2- J = 8.4 Hz, IH), 7.74 (d, J = 6.6 Hz, IH), Morpholin-4-yl-ethyl) -7.55 (m, 2H), 3.79 (m, 4H), 3.67 (t, amide J = 6.6 Hz, 2H), 2.91 (t, J = 6.6 Hz, 2H),
2.85(m, 4H), 2.23(m, IH), 1.29- 1.18(m, 4H)  2.85 (m, 4H), 2.23 (m, IH), 1.29-1.18 (m, 4H)
¾ NMR (300 MHz, DMS0_d6) 10.32 (s, 피를리딘 -2-카르복실산 ¾ NMR (300 MHz, DMS0_d 6 ) 10.32 (s, pyridine-2-carboxylic acid
IH), 9.96 (s, IH), 9.14 (s, IH), 8.75  IH), 9.96 (s, IH), 9.14 (s, IH), 8.75
[2-(2- (s, IH), 8.28 (s, IH), 7.83 (d, J=8.7 트리플루오로메틸 -3H- Hz, IH), 7.63 (s, 2H), 7.44 (d, J=9.0 [2- (2- (s, IH), 8.28 (s, IH), 7.83 (d, J = 8.7 trifluoromethyl-3H- Hz, IH), 7.63 (s, 2H), 7.44 (d, J = 9.0
442.4 벤즈이미다졸 -5- 442.4 Benzimidazole-5
Hz, IH), 3.76 (dd, J=8.4, 5.7 Hz, 일아미노) -퀴나졸린 -7- IH), 2.91 (t, J=6.6 Hz, 2H), 2.08 (m, 일] -아미드 Hz, IH), 3.76 (dd, J = 8.4, 5.7 Hz, monoamino) -quinazolin-7-IH), 2.91 (t, J = 6.6 Hz, 2H), 2.08 (m, day] -amide
IH), 1.81 (m, IH), 1.67 (m, 2H)  IH), 1.81 (m, IH), 1.67 (m, 2H)
JH NMR (300 MHz, DMS0-d6) 9.63 (brs, J H NMR (300 MHz, DMS0-d 6 ) 9.63 (brs,
N2-(2- IH), 8.79 (s, IH), 8.64 (s, IH), 7.61 트리플루오로메틸 -3H- (brs, IH), 7.52 (d, J=8.7 Hz, IH), 벤즈이미다졸 -5-일 )ᅳ 345.3 N 2 - (2- IH), 8.79 (s, IH), 8.64 (s, IH), 7.61 to trifluoromethyl -3H- (brs, IH), 7.52 (d, J = 8.7 Hz, IH), benzamide Imidazole-5-day) ᅳ 345.3
6.70 (dd, J=8.4, 1.8 Hz, IH), 6.55 퀴나졸린 -2,7- (s, IH), 6.19 (brs, 2H)  6.70 (dd, J = 8.4, 1.8 Hz, IH), 6.55 quinazoline -2,7- (s, IH), 6.19 (brs, 2H)
다이아민 Diamine
¾ NMR (300 MHz, DMSO, δ ) ： ¾ NMR (300 MHz, DMSO, δ) ：
2-(2-사이클로프로필- 9.31(s, IH), 8.81(br s, IH), 8.40(br  2- (2-cyclopropyl-9.31 (s, IH), 8.81 (br s, IH), 8.40 (br
3H-벤즈이미다졸 -5- s,lH), 8.17(s, 2H), 8.07(s, IH), 3H-benzimidazole-5-s, lH), 8.17 (s, 2H), 8.07 (s, IH),
일아미노) -퀴나졸린 -7- 7.91(d, IH), 7.75(d, IH), 7.50(m, Monoamino) -quinazolin-7-7.91 (d, IH), 7.75 (d, IH), 7.50 (m,
456 카르복실산 (2- IH), 7.42(m, IH), 2.75(t, 2H),  456 carboxylic acid (2-IH), 7.42 (m, IH), 2.75 (t, 2H),
피페리딘 -1-일-에틸) - 2.55(m, 4H), 2. Km, IH), 1.80(m, 2H), 아미드 1.53(m, 4H), 1.40(m, 2H), 1.10- 0.90(m, 4H) ¾ NMR (300 MHz, DMS0-d6) 11.45 (s, 피를리딘 -2-카르복실산 IH), 10.14 (s, IH), 9.30 (s, IH), Piperidin-1-yl-ethyl) -2.55 (m, 4H), 2.Km, IH), 1.80 (m, 2H), amide 1.53 (m, 4H), 1.40 (m, 2H), 1.10-0.90 (m, 4H) ¾ NMR (300 MHz, DMS0-d 6 ) 11.45 (s, pyridine-2-carboxylic acid IH), 10.14 (s, IH), 9.30 (s, IH),
[2-(2- 8.77 (d, J=6.6 Hz, IH), 8.18 (s, IH), 트리플루오로메틸 -3H- 8.05 (s, IH), 7.71 (d, J=9.0 Hz, IH), (2- (2- 8.77 (d, J = 6.6 Hz, IH), 8.18 (s, IH), trifluoromethyl-3H-8.05 (s, IH), 7.71 (d, J = 9.0 Hz, IH) ,
442.3 벤즈이미다졸 -5- 7.59 (dd, J=8.1, 0.9 Hz, IH), 7.33 일아미노) -퀴나졸린 -8- (t, J=7.8 Hz, IH), 3.92 (dd, J=9.0, 일]—아미드 5.1 Hz, IH), 2.89 (m, 2H) , 2.12 (m, 442.3 benzimidazole-5.59 ( dd, J = 8.1, 0.9 Hz, IH), 7.33 monoamino) -quinazolin- 8- (t, J = 7.8 Hz, IH), 3.92 (dd, J = 9.0, General] —amide 5.1 Hz, IH), 2.89 (m, 2H), 2.12 (m,
IH), 1.89 (m, IH), 1.61 (m, 2H)  IH), 1.89 (m, IH), 1.61 (m, 2H)
모폴린 -4—일 -[2— (2- ¾ NMR (300 MHz, DMSO, δ ) ： Morpholine -4-day-[2-(2-¾ NMR (300 MHz, DMSO, δ) ：
트리플루오로메틸 -3H- 10.15(s, IH), 9.36(s, IH), 8.68(s, 벤즈이미다졸 -5- IH), 7.99(d, J =8.4Hz, IH), 7.73- 443.1 일아미노) -퀴나졸린 -7- 7.61(m, 3H), 7.35(d, J=8.1Hz, IH) , 일] -메탄온 3.66-3.55(m, 8H) Trifluoromethyl-3H-10.15 (s, IH), 9.36 (s, IH), 8.68 (s, benzimidazole-5-IH), 7.99 (d, J = 8.4Hz, IH), 7.73-443.1 days Amino) -quinazolin-7- 7.61 (m, 3H), 7.35 (d, J = 8.1Hz, IH), general] -methanone 3.66-3.55 (m, 8H)
¾ NMR (300 MHz, DMS0-d6) 9.96 (s, ¾ NMR (300 MHz, DMS0-d 6 ) 9.96 (s,
5-[2-(2-메틸-311- IH), 9.14 (s, IH), 8.68 (s, IH), 8.18 벤즈이미다졸 -5- (s, IH), 7.83 (d, J=8.7 Hz, IH), 7.68 일아미노) -퀴나졸린 -그 445.2  5- [2- (2-Methyl-311-IH), 9.14 (s, IH), 8.68 (s, IH), 8.18 benzimidazole -5- (s, IH), 7.83 (d, J = 8.7 Hz , IH), 7.68 monoamino) -quinazolin-he 445.2
(m, 2H), 7.07 (d, J=1.8 Hz, IH), 7.01 일옥시메틸] - (dd, J=8.4, 2.4 Hz, 1H)( 4.97 (m, (m, 2H), 7.07 (d, J = 1.8 Hz, IH), 7.01 yloxymethyl]-(dd, J = 8.4, 2.4 Hz, 1H) ( 4.97 (m,
옥사졸리딘 _2_온 Oxazolidine _ 2 _ On
IH), 4.32 (m, 2H), 3.60 (m, 2H)  IH), 4.32 (m, 2H), 3.60 (m, 2H)
¾ NMR (300 MHz, DMSO, δ ) ：  ¾ NMR (300 MHz, DMSO, δ) ：
(7-클로로 -2- 10.08(s, IH), 9.26(s, IH), 8.64(s, 사이클로프로필 -3- IH), 7.76-7.69(m, 2H), 7.64(s, IH), 메틸— 3H-벤즈이미다졸ᅳ 364.3  (7-chloro-2- 10.08 (s, IH), 9.26 (s, IH), 8.64 (s, cyclopropyl-3-IH), 7.76-7.69 (m, 2H), 7.64 (s, IH), methyl — 3H-benzimidazole ᅳ 364.3
7.28(t, J =7.2Hz, IH), 3.83(s, 3H) ,  7.28 (t, J = 7.2 Hz, IH), 3.83 (s, 3H),
5ᅳ일) -(8-메틸ᅳ  5 ᅳ day)-(8-methyl ᅳ
2.68(s, 3H), 2.26-2.21(m( IH) , 1.07- 퀴나졸린 -2-일)—아민 2.68 (s, 3H), 2.26-2.21 (m ( ih), 1.07-quinazolin-2-yl) —amine
1.03(m, 4H) [7-(l-메틸-피페리딘-1.03 (m, 4H) [7- (l-methyl-piperidine-
]H NMR (300 MHz, DMS0-d6) 9.85 (s, ] H NMR (300 MHz, DMS0-d 6 ) 9.85 (s,
4-일옥시) -퀴나졸린 -2- 4-yloxy) -quinazolin-2-
1H), 9.01 (s, 1H), 8.50 (s, 1H)( 8.17 일] -(2-1H), 9.01 (s, 1H), 8.50 (s, 1H) ( 8.17 days)-(2-
92 (s, 1H), 7.69 (m, 4H), 7.81 (d, J=8.7 443.3 트리플루오로메틸ᅳ 3H- Hz, 1H), 5.06 (m, 1H), 4.30 (s, 4H), 벤즈이미다졸 -5-일) - 2.71 (t, J=6.9 Hz, 4H), 2.32 (s, 3H) 아민 92 (s, 1H), 7.69 (m, 4H), 7.81 (d, J = 8.7 443.3 trifluoromethyl ᅳ 3H- Hz, 1H), 5.06 (m, 1H), 4.30 (s, 4H), benzimi Dazol-5-yl) -2.71 (t, J = 6.9 Hz, 4H), 2.32 (s, 3H) amine
실시예 VI: 벤즈이미다졸유도체 -(3) Example VI Benzimidazole Derivatives-(3)
벤즈이미다졸의 유도체중 2번 위치로의 헤테로원소 치환기 도입은 다음과 같은 반웅을 이용하였다. 합성밥법은 문헌 [J. Med. Chew. 2008, 51, 875-896]에 기재된 합성 방법을 이용하였다.  Introduction of the heteroatom substituent to the position 2 of the derivative of benzimidazole was used as the following reaction. Synthetic rice method is described in J. Med. Chew. 2008, 51, 875-896 were used.
Figure imgf000116_0001
Figure imgf000116_0001
상기 실시예 VI에서 제조한 벤즈이미다졸 화합물을 이용하여 실시예 동일한 방식으로 수행하여 하기 표 6에 기재된 실시예의 화합물을 제조하였다. Using the benzimidazole compound prepared in Example VI was carried out in the same manner as in Example to prepare the compounds of the examples described in Table 6 below.
[표 6] TABLE 6
Figure imgf000117_0001
'ᅳ 융 ίο 륭&^ & (ta{p ¾-bFo ^융 ^
Figure imgf000118_0001
Figure imgf000117_0001
' ᅳ Yung ίο Long & ^ & (ta { p ¾-bFo ^ Yung ^
Figure imgf000118_0001
Figure imgf000118_0002
Figure imgf000118_0002
Ι'όΙ/.ΟΟ/ΐΙΟΖΗΜ/ΙΟΛ Ι'όΙ / .ΟΟ / ΐΙΟΖΗΜ / ΙΟΛ
Figure imgf000119_0001
Figure imgf000119_0001
Figure imgf000119_0002
Figure imgf000119_0002
단계 1: 1-메틸 -3-니트로벤조산 메틸에스터 Step 1: 1-methyl-3-nitrobenzoic acid methyl ester
2-메틸— 3-니트로벤조산 (2g, 11.04隱 ol)을 메탄을 (20ml)에 용해시킨 후 S0Cl2(3ml)를 적가하였다. 이 반응 혼합물을 2시간 동안 환류 교반 후 감압농축하였다. 여액을 물로 회석한 후 MC로 추출하여 무수 MgS04 를 이용하여 건조시킨 후 감압 농축하였다. 남은 유기물질을 실리카와 n-핵산 /EA(4/1) 용매를 이용한 칼럼 크로마토그래피법을 통해 1—메틸 -3-니트로벤조산 메틸에스터를 (1.91g) 89%수을로 얻었다. ' 2-methyl- 3-nitrobenzoic acid (2 g, 11.04 'ol) was dissolved in methane (20 ml) and SOCl 2 (3 ml) was added dropwise. The reaction mixture was concentrated under reduced pressure after stirring under reflux for 2 hours. The filtrate was diluted with water, extracted with MC, dried over anhydrous MgS0 4, and concentrated under reduced pressure. The remaining organic material was purified by column chromatography using silica and a solvent of n-nucleic acid / EA (4/1) to obtain 1-methyl-3-nitrobenzoic acid methyl ester (1.91 g) as 89% water. '
¾ 醒 R(300MHz, CDC13); 8.00(d, J=8.1 Hz, 1H)， 7.84(d, J=8.1 Hz, 1H),¾ 醒 R (300 MHz, CDC1 3 ); 8.00 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H),
7.39(t, J=8.1 Hz, 1H), 3.94(s, 3H), 2.63(s, 3H). 단계 2: 1—메틸 -3-아미노벤조산 메틸에스터 7.39 (t, J = 8.1 Hz, 1 H), 3.94 (s, 3 H), 2.63 (s, 3 H). Step 2: 1—Methyl-3-Aminobenzoic Acid Methylester
1-메틸 -3-니트로벤조산 메틸에스터 (1.8 g)를 메탄을 (16ml)에 용해시킨 후 Pd/C(10 %)을 촉매량 첨가하여 수소하에서 4시간동안 교반하였다. 반응 혼합물을 셀라이트를 통해 여과후 여액을 감압 농축하여 칼럼 크로마토그래피법을 통해 1- 메틸 -3-아미노벤조산 메틸에스터 (1.44g)를 95% 수율로 얻었다.  1-Methyl-3-nitrobenzoic acid methyl ester (1.8 g) was dissolved in methane (16 ml), and then catalytic amount of Pd / C (10%) was added and stirred under hydrogen for 4 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give 1-methyl-3-aminobenzoic acid methyl ester (1.44 g) in 95% yield through column chromatography.
LCMSCM+1; 166). 단계 3: 1—메틸 -3-아미노 -5-니트로벤조산 메틸에스터 LCMSCM + 1; 166). Step 3: 1—Methyl-3-amino-5-nitrobenzoic acid methylester
1-메틸 -3-아미노벤조산 메틸에스터 (1.15g, 6.96誦01)를 0°C에서 발연 황산 (7ml)에 용해시킨 후 발연 질산 (0.32ml, 7.66隱01)을 내부온도가 20°C를 넘지 않도록 주의해서 서서히 적가하였다. 이 반응 혼합물을 lO20r의 온도를 유지하며 90분동안 교반 후 얼음물에 첨가하였다. EA를 이용 유기물을 추출하고 물로 유기층을 2회 세척한 후 무수 Na2S¾로 건조하고 감압 농축하였다. 생성된 고체를 소량의 차가운 EA 로 세척하여 주황색 고체상태의 1-메틸 -3-아미노 -5-니트로벤조산 메틸에스터 (1.03g)를 70.5%수율로 얻었다. Dissolve 1-methyl-3-aminobenzoic acid methyl ester (1.15g, 6.96 誦 01) in fuming sulfuric acid (7ml) at 0 ° C, and then fuming nitric acid (0.32ml, 7.66 隱0 1) at 20 ° C Carefully added dropwise so as not to exceed. The reaction mixture was stirred for 90 minutes while maintaining the temperature of 1020r and added to ice water. The organics were extracted using EA, washed twice with water, dried over anhydrous Na 2 S¾ and concentrated under reduced pressure. The resulting solid was washed with a small amount of cold EA to give 1-methyl-3-amino-5-nitrobenzoic acid methyl ester (1.03 g) as an orange solid in 70.5% yield.
]H 画 R (300MHz , CDC13); 8.84(s, 1H)， 8.68(s, 1H), 4.01(s, 3H), 2.75(s, ] H画R (300MHz, CDC13 ); 8.84 (s, 1H), 8.68 (s, 1H), 4.01 (s, 3H), 2.75 (s,
3H). 단계 4: 6-나트로 -1H-인다졸 -4-카르복실산 메틸에스터 3H). Step 4: 6-Natro-1H-indazole-4-carboxylic acid methyl ester
1-메틸 -3-아미노 -5-니트로벤조산 메틸에스터 (620mg, 2.95隱01)를 빙초산 (16ml)에 녹인 용액을 얼음중탕으로 넁각시키면서 NaN02(214mg, 3.1mmol)를 물 (2ml)에 녹인 수용액을 첨가하고 1시간동안 교반한다. 반응 혼합물의 은도를 상온으로 올린 후 감압 농축한다. 남은 물질을 물에 적가하고 0°C에서 15분간 교반한다. 생성된 고체를 여과하여 얻고 이를 물로 세척하여 옅은 주황색의 6- 나트로 -1H-인다졸 -4-카르복실산 메틸에스터 (469mg)를 72%수율로 얻었다. A solution of 1-methyl-3-amino-5-nitrobenzoic acid methyl ester (620mg, 2.95 隱0 1) dissolved in glacial acetic acid (16ml) was added to an ice bath. NaN0 2 (214mg, 3.1mmol) was added to water (2ml). The dissolved aqueous solution is added and stirred for 1 hour. The silver content of the reaction mixture was raised to room temperature and then concentrated under reduced pressure. The remaining material is added dropwise to water and stirred at 0 ° C for 15 minutes. The resulting solid was filtered off and washed with water to give a pale orange 6-natro-1H-indazole-4-carboxylic acid methyl ester (469 mg) in 72% yield.
]H NMR (300MHz, DMS0-d6)； 14.01(s, 1H), 8.69(s, 1H), 8.57(s, 1H)， 8.42(s, 1H), 3.98(s, 3H) . 상기 실시예 VII에서 제조한 인다졸 화합물 및 각각 상응하는 출발물질을 이용하여 실시예 IV와 동일한 방식으로 수행하여 하기 표 7에 기재된 실시예의 화합물을 제조하였다. 021 ] H NMR (300 MHz, DMS0-d 6 ); 14.01 (s, 1H), 8.69 (s, 1H), 8.57 (s, 1H), 8.42 (s, 1H), 3.98 (s, 3H). Using the indazole compounds prepared in Example VII and the corresponding starting materials, respectively, the compounds of the examples described in Table 7 were prepared in the same manner as in Example IV. 021
Figure imgf000121_0001
Figure imgf000121_0001
[L Έ] t?6TZ-00/llOZaM/X3d 2H-인다졸 -4—일] -모폴린- IH), 7.92(s, 1H), 7.80-7.72 (m, [L Έ] t? 6TZ-00 / llOZaM / X3d 2H-indazol-4—yl] -morpholine-IH), 7.92 (s, 1H), 7.80-7.72 (m,
4-일-메탄온 2H), 7.37-7.30(ni, 2H), 4.43(q,  4-yl-methanone 2H), 7.37-7.30 (ni, 2H), 4.43 (q,
J-7.5Hz, 2H), 3.62(m, 4H), 3.34(m, 4H), 2.71(s, 3H), 1.45(t, J=7.5Hz, 3H)  J-7.5 Hz, 2H), 3.62 (m, 4H), 3.34 (m, 4H), 2.71 (s, 3H), 1.45 (t, J = 7.5 Hz, 3H)
¾ NM (300 MHz, DMSO, δ ) ：  ¾ NM (300 MHz, DMSO, δ) ：
10.03(s, IH), 9.28(s, IH), 8.82(s,  10.03 (s, IH), 9.28 (s, IH), 8.82 (s,
[1-에틸ᅳ 6-(8-메틸- IH), 8.30(s, IH), 7.77-7.69(ni,  [1-ethyl ᅳ 6- (8-methyl-IH), 8.30 (s, IH), 7.77-7.69 (ni,
퀴나졸린 -2-일아미노) - Quinazolin-2-ylamino)-
177 2H), 7.42(s, IH), 7.29(t, J=7.5Hz, 417.3 1H-인다졸 -4-일] -모폴린- IH), 4.41(q, J=7.5Hz, 2H), 3.62- 4-일-메탄은 177 2H), 7.42 (s, IH), 7.29 (t, J = 7.5 Hz, 417.3 1H-indazol-4-yl] -morpholine- IH), 4.41 (q, J = 7.5 Hz, 2H), 3.62 4-yl-methane is
3.51(m, 8H), 2.67(s, 3H), 1.49(t,  3.51 (m, 8H), 2.67 (s, 3H), 1.49 (t,
J=7.2Hz, 3H)  J = 7.2Hz, 3H)
¾ NMR (300 MHz, DMSO, δ ) ：  ¾ NMR (300 MHz, DMSO, δ) ：
10.08(s, IH), 9.29(s, IH), 8.69- 보폴린 -4-카르복실산 [2- 8.66(m, 2H), 7.92(s, IH), 7.78- 에틸ᅳ6-(8-메틸- 7.71(m, 2H), 7.39(s, IH), 7.31(t,  10.08 (s, IH), 9.29 (s, IH), 8.69-Bopolin-4-carboxylic acid [2- 8.66 (m, 2H), 7.92 (s, IH), 7.78-ethyl ᅳ 6- (8- Methyl-7.71 (m, 2H), 7.39 (s, IH), 7.31 (t,
181 432.2 퀴나졸린 -2-일아미노) - J =7.8Hz, IH), 4.37(q, J=7.2Hz,  181 432.2 Quinazolin-2-ylamino) -J = 7.8 Hz, IH), 4.37 (q, J = 7.2 Hz,
2H-인다졸 -4-일] -아미드 2H), 3.65-3.62 (m, 4H), 3.49- 3.46(m, 4H), 2.71(s, 3H), 1.41(t,  2H-indazol-4-yl] -amide 2H), 3.65-3.62 (m, 4H), 3.49-3.46 (m, 4H), 2.71 (s, 3H), 1.41 (t,
J=7.2Hz, 3H)  J = 7.2Hz, 3H)
]H NMR (300 MHz, DMSO, 5 ) ： ] H NMR (300 MHz, DMSO, 5) ：
1-에틸 -6-(8-메틸- 10.38(s, IH), 10.05(sᅳ IH) ,  1-ethyl-6- (8-methyl-10.38 (s, IH), 10.05 (s ᅳ IH),
퀴나졸린 -2-일아미노) - 9.30(s, IH), 8.74(s, IH), 8.48(s,  Quinazolin-2-ylamino)-9.30 (s, IH), 8.74 (s, IH), 8.48 (s,
182 1H-인다졸—4-카르복실산 526.2  182 1H-indazole—4-carboxylic acid 526.2
IH), 8.14(s, IH), 7.78-7.69 (m,  IH), 8.14 (s, IH), 7.78-7.69 (m,
(3-플루오로— 5-모폴린 -4- 2H), 7.33-7.18(m, 3H), 6.56- 일-페닐) -아미드  (3-fluoro— 5-morpholine-4- 2H), 7.33-7.18 (m, 3H), 6.56- yl-phenyl) -amide
6.52(m, IH), 4.45(q, J=7.5Hz, 2H)， 3.73(πι, 4H), 3.12(m, 4H), 2.65(s, 6.52 (m, IH), 4.45 (q, J = 7.5 Hz, 2H), 3.73 (πι, 4H), 3.12 (m, 4H), 2.65 (s,
3H), 1.51(t, J=7.5Hz, 3H) 실시예 VII: 벤조트리아졸유도체  3H), 1.51 (t, J = 7.5 Hz, 3H) Example VII: Benzotriazole derivatives
실시예에 사용된 벤조트리아졸 유도체는 아래 합성법을 이용하였다.  The benzotriazole derivatives used in the examples used the following synthesis method.
Figure imgf000123_0001
Figure imgf000123_0001
6-니트로 -1H-벤조트리아졸 -4-카르복실산의 합성 Synthesis of 6-nitro-1H-benzotriazole-4-carboxylic acid
2, 3-다이아미노— 5-니트로 벤조산 (600mg, 1 equiv.)을 아세트산 (8ml)에 녹인 후， NaN02를 물 (4ml)에 녹인 용액을 0°C에서 서서히 적가하였다. 이 반웅 혼합물을 상은에서 1시간 동안 교반 후， 감압 농축하였다. EA로 희석한 후 물로 세척하여 무수 ¾¾3¾로 건조하고 감압 농축하여 얻은 물질을 실리카와 MC/MeOH=10/l 용매를 사용한 크로마토그래피법을 이용하여 6-니트로 -1H-벤조트리아졸 -4- 카르복실산 (620mg)을 97¾) 수율로 얻었다. 2, 3-diamino- 5-nitro benzoic acid (600 mg, 1 equiv.) Was dissolved in acetic acid (8 ml), then a solution of NaN0 2 in water (4 ml) was slowly added dropwise at 0 ° C. The reaction mixture was stirred for 1 hour at phase silver, and then concentrated under reduced pressure. After diluting with EA, washing with water, drying with anhydrous ¾¾3¾ and concentrating under reduced pressure, the obtained material was chromatographed using silica and MC / MeOH = 10 / l solvent, using 6-nitro-1H-benzotriazole-4-carboxamide. Acid ( 620 mg ) was obtained in 97¾) yield.
상기 실시예 VII에서 제조한 벤조트리아졸 화합물 Benzotriazole Compounds Prepared in Example VII
출발물질을 이용하여 실시예 IV와 동일한 방식으로 하기 표 The following table in the same manner as in Example IV using the starting material
화합물을 제조하였다. [표 8] The compound was prepared. TABLE 8
Figure imgf000124_0001
실험예: Master cell에서 Syk활성 저해효과시험 방법 및 분석
Figure imgf000124_0001
Experimental Example: Method and analysis of inhibitory effect on Syk activity in master cell
비만 세포 (Master cell)에서 Syk 활성이 저해되면 히스타민과 같은 매개체 (mediator) 및 지질 매개체의 생산， 또는. 사이토카인 (cytokine)의 분비가 감소한다 (Wong et al. , Expert Opin Invest ig Drugs. , 2004 Jul； 13(7)： 743-62) . 히스타민 방출 (Histamine release) 실험은 하이노넨의 방법 (Heinonen J.E. et al. FEBS Letters., 527， 2002, 274-278)에 근거하여 실시하였으며 , 히스타민의 양은 효소 면역분석법 (enzyme immunoassay)을 이용하여 실시하였다. 구체적으로， RBL-2H3 비만 세포를 10%(w/v) FBS가 첨가된 DMEM 배지에서 배양한 후 96 웰 플레이트에 각 웰당 10,000개 세포를 분주하여 5% C02 및 37 °C 조건의 배양기에서 24시간 동안 배양하였다. 상기에서 배양된 세포에 단일클론 항- DNP(monoclonal anti-DNP, sigma사) 500 ng/ml 및 100%(v/v) 디메틸설폭사이드 (DMS0)에 녹인 본원 발명의 실시예에 따른 화합물을 각각 0.001 uM, 0.01 uM, 0.1 uM, 1.0 uM 및 10 uM농도로 함께 처리하였다. 이때， 대조군으로 디메틸설폭사이드를 화합물 처리시 사용한 퍼센트와 같은 양을 처리하였다. 그 후 5% C02 및 37°C의 배양기에서 24시간 동안 배양하였다. 이 후 EIA 히스타민 키트 (I瞧 unotech사)를 제조사의 권고에 따라 이용하였으며， 배양이 끝난 플레이트에 50 ul .히스타민 분비 버퍼 (histamine release buffer)를 각 웰 당 50ul씩 처리한 후 37°C에서 30분 동안 반웅시켰다. 이어， 반응이 끝난 플레이트의 배지를 각 웰당 100 ul씩 새로운 플레이트에 옮기고 25ul 아세틸화 버퍼 (acetylation buffer) 및 25 ul 아세틸화 시약 (acetylat ion reagent)을 넣어 충분히 섞어 주었다. 상기에서 제조한 아세틸화 시료 중 50 ul를 항체가 코팅된 플레이트로 옮기고 200 ul 접합체 (conjugate)를 넣어 섞어준 후， 4°C에서 18시간 동안 반응 시켰다. 반응이 끝난 플레이트의 시료를 모두 제거하고 세척 버퍼 (washing buffer)를 200 ul 첨가하여 3번 세척한 후, 200. ul 기질 (substrate)을 첨가하여 상온에서 30분 동안 반웅시켰다. When Syk activity is inhibited in master cells, production of histamine-like mediators and lipid mediators; or. Secretion of cytokines is reduced (Wong et al., Expert Opin Invest ig Drugs., 2004 Jul; 13 (7): 743-62). Histamine release experiments were performed based on Heinen JE et al. FEBS Letters., 527, 2002, 274-278, and the amount of histamine was carried out using an enzyme immunoassay. It was. Specifically, RBL-2H3 mast cells were cultured in DMEM medium supplemented with 10% (w / v) FBS and then dispensed 10,000 cells per well into 96-well plates at 5% CO 2 and 37 ° C. Incubated for 24 hours in the condition incubator. Compounds according to the embodiment of the present invention dissolved in monoclonal anti-DNP (monoclonal anti-DNP, sigma) 500 ng / ml and 100% (v / v) dimethyl sulfoxide (DMS0) in the cultured cells, respectively Treated together with 0.001 uM, 0.01 uM, 0.1 uM, 1.0 uM and 10 uM concentrations. At this time, as a control, the same amount of dimethyl sulfoxide as used in compound treatment was treated. It was then incubated for 24 hours in incubator at 5% CO 2 and 37 ° C. Thereafter, EIA histamine kit (I 瞧 unotech Co., Ltd.) was used according to the manufacturer's recommendation, and 50 ul of histamine release buffer was treated with 50 ul of each well for 30 wells at 37 ° C. Reaction for minutes. Subsequently, the medium of the reaction plate was transferred to a new plate with 100 ul of each well, and 25ul acetylation buffer and 25 ul acetylation ion reagent were added and mixed well. 50 ul of the acetylated sample prepared above was transferred to an antibody-coated plate, mixed with 200 ul conjugate (conjugate), and reacted at 4 ° C. for 18 hours. Remove all the samples from the reaction plate and wash three times by adding 200 ul of washing buffer (200) . ul substrate was added to react for 30 minutes at room temperature.
이어， 상기 반응액에 50ul 정지액 (stop solution)을 첨가하여 반응을 종료한 후， 벤크마크 플러스 (Benchmark plus, Biorad사) 장비를 사용하여 406 nm에서 흡광도를 측정하였다. 화합물을 처리하지 않은 대조군 세포의 흡광도를 기준으로 각 화합물들의 처리 농도에 따른 히스타민 방출 정도를 산출하였다. EC50(nM) 값은 히스타민 방출을 50% 억제하는 각 화합물의 농도를 산출한 것으로， 엑셀 그래픽 프로그램 (Excel graphic program)을 이용하였다. 한편， 화합물들의 억제 활성을 스크리닝 (screening)하기 위해서， 퍼센트 저해효과 (percent inhibition)를 측정하였다. 실험 방법은 상기와 동일하며， 이때, 처리한 화합물은 0.01 uM 및 0.1 uM의 농도로 사용하였다. 퍼센트 저해 효과 산출 방법 역시 화합물을 처리하지 않은 대조군 세포의 흡광도를 기준으로 히스타민 방출 정도를 상대적 산출하여 나타내었다 . 상기에서 측정된 화합물의 EC50(nM) 결과를 하기 표 9에 나타내었다 . Subsequently, after the reaction was terminated by adding a 50ul stop solution to the reaction solution, absorbance was measured at 406 nm using a Benckmark Plus (Benchmark plus, Biorad) equipment. The degree of histamine release according to the treatment concentration of each compound was calculated based on the absorbance of the control cells not treated with the compound. The EC 50 (nM) value calculated the concentration of each compound that inhibits histamine release by 50%, using an Excel graphic program. Meanwhile, in order to screen the inhibitory activity of the compounds, the percent inhibition was measured. Experimental method was the same as above, wherein the treated compound was used at concentrations of 0.01 uM and 0.1 uM. The method of calculating the percent inhibitory effect is also based on the absorbance of the control cells without treatment with the compound. Relative degrees of release are shown. EC 50 (nM) results of the compounds measured above are shown in Table 9 below.
[표 9] TABLE 9
Figure imgf000126_0001
18 측정하지 않음 38
Figure imgf000126_0001
18 Not measured 38
19 측정하지 않음 1.819 Not measured 1.8
20 측정하지 않음 0.320 Not measured 0.3
21 측정하지 않음 30.321 Not measured 30.3
22 측정하지 않음 43.622 No measurement 43.6
23 축정하지 않음 49.523 No Axis 49.5
24 측정하지 않음 39.724 Not measured 39.7
25 측정하지 않음 측정하지 않음25 Not measured Not measured
26 측정하지 않음 36. 126 Not measured 36. 1
27 측정하지 않음 3827 Not measured 38
28 측정하지 않음 41. 128 Not measured 41. 1
29 ' 측정하지 않음 46.629 '' Not measured 46.6
30 측정하지 않음 40.730 Not measured 40.7
31 측정하지 않음 33.431 Not measured 33.4
32 측정하지 않음 58.732 Not measured 58.7
33 측정하지 않음 36.433 Not measured 36.4
34 측정하지 않음 측정하지 않음34 Not measured Not measured
35 측정하지 않음 34.635 Not measured 34.6
36 측정하지 않음 53.436 Not measured 53.4
37 측정하지 않음 48.737 Not measured 48.7
38 측정하지 않음 44.938 Not measured 44.9
39 측정하지 않음 52.839 Not measured 52.8
40 측정하지 않음 측정하지 않음 41 측정하지 않음 51.840 not measured not measured 41 Not measured 51.8
42 33 60.342 33 60.3
43 ᅳ 60 54. 143 ᅳ 60 54. 1
44 측정하지 않음 41.844 Not measured 41.8
45 측정하지 않음 40.845 Not measured 40.8
46 90 53.346 90 53.3
47 측정하지 않음 측정하지 않음47 Not measured Not measured
48 측정하지 않음 측정하지 않음48 not measured not measured
49 25 57.449 25 57.4
50 측정하지 않음 측정하지 않음50 not measured not measured
51 측정하지 않음 50.851 Not measured 50.8
52 측정하지 않음 42.852 Not measured 42.8
53 측정하지 않음 43, 253 Not measured 43, 2
54 측정하지 않음 40.554 Not measured 40.5
55 측정하지 않음 50.855 Not measured 50.8
56 측정하지 않음 49.756 Not measured 49.7
57 측정하지 않음 51. 157 Not measured 51. 1
58 측정하지 않음 52.958 Not measured 52.9
59 40 52.359 40 52.3
60 측정하지 않음 48.460 Not measured 48.4
61 40 60.961 40 60.9
62 측정하지 않음 46.662 Not measured 46.6
63 측정하지 않음 44.5 64 42 58.563 Not measured 44.5 64 42 58.5
65 측정하지 않음 44.865 Not measured 44.8
66 측정하지 않음 49.366 Not measured 49.3
67 90 52.667 90 52.6
68 측정하지 않음 33. 168 Not measured 33. 1
69 측정하지 않음 41.769 Not measured 41.7
70 측정하지 않음 50.570 Not measured 50.5
71 측정하지 않음 47.971 Not measured 47.9
72 측정하지 않음 34.572 Not measured 34.5
73 측정하지 않음 43.673 Not measured 43.6
74 40 57.974 40 57.9
75 80 51.275 80 51.2
76 측정하지 않음 50.776 Not measured 50.7
77 50 측정하지 않음77 50 Not measured
78 측정하지 않음 45.778 Not measured 45.7
79 40 측정하지 않음79 40 Not measured
80 150 5180 150 51
81 측정하지 않음 5181 Not measured 51
82 측정하지 않음 42. 182 Not measured 42. 1
83 30 측정하지 않음83 30 Not measured
84 45 측정하지 않음84 45 Not measured
85 60 측정하지 않음85 60 Not measured
86 40 측정하지 않음 87 70 측정하지 않음86 40 Not measured 87 70 Not measured
88 100 측정하지 않음88 100 Not measured
89 50 측정하지 않음89 50 Not measured
90 측정하지 않음 측정하지 않음90 not measured not measured
91 2500 측정하지 않음91 2500 Not measured
92 50 측정하지 않음92 50 Not measured
93 1500 측정하지 않음93 1500 Not measured
94 180 측정하지 않음94 180 Not measured
95 150 측정하지 않음95 150 Not measured
96 50 측정하지 않음96 50 Not measured
97 60 측정하지 않음97 60 Not measured
98 50 측정하지 않음98 50 Not measured
99 40 측정하지 않음99 40 Not measured
100 90 측정하지 않음100 90 Not measured
101 120 측정하지 않음101 120 Not measured
102 180 측정하지 않음102 180 Not measured
103 300 측정하지 않음103 300 Not measured
104 40 측정하지 않음104 40 Not measured
105 90 측정하지 않음105 90 Not measured
106 70 측정하지 않음106 70 Not measured
107 60 측정하지 않음107 60 not measured
108 45 측정하지 않음108 45 Not measured
109 300 측정하지 않음 110 100 측정하지 않음109 300 not measured 110 100 Not measured
111 100 측정하지 않음111 100 Not measured
112 40 측정하지 않음112 40 Not measured
113 50 측정하지 않음113 50 Not measured
114 60 측정하지 않음114 60 Not measured
115 40 측정하지 않음115 40 Not measured
116 30 측정하지 않음116 30 not measured
117 150 측정하지 않음117 150 Not measured
118 70 측정하지 않음118 70 Not measured
119 65 측정하지 않음119 65 Not measured
120 30 측정하지 않음120 30 Not measured
121 40 측정하지 않음121 40 Not measured
122 55 측정하지 않음122 55 Not measured
123 30 측정하지 않음123 30 does not measure
124 70 측정하지 않음124 70 Not measured
125 70 측정하지 않음125 70 Not measured
126 40 측정하지 않음126 40 Not measured
127 70 측정 하지 않음127 70 Not measured
128 80 측정하지 않음128 80 not measured
129 35 측정하지 않음129 35 Not measured
130 50 측정하지 않음130 50 Not measured
131 30 측정하지 않음131 30 does not measure
132 150 측정하지 않음 133 90 측정하지 않음132 150 Not measured 133 90 not measured
134 ' 40 측정하지 않음134 '40 Not measured
135 80 측정하지 않음135 80 Not measured
136 40 측정하지 않음136 40 Not measured
137 60 측정하지 않음137 60 not measured
138 45 측정하지 않음138 45 not measured
139 40 측정하지 않음139 40 Not measured
140 30 측정하지 않음140 30 Not measured
141 35 측정하지 않음141 35 not measured
142 50 측정하지 않음142 50 not measured
143 100 측정하지 않음143 100 not measured
144 45 측정하지 않음144 45 not measured
145 40 측정하지 않음145 40 Not measured
146 100 측정하지 않음146 100 Not measured
147 45 , 측정하지 않음147 45, not measured
148 50 측정하지 않음148 50 Not measured
149 100 측정하지 않음149 100 Not measured
150 100 측정하지 않음150 100 Not measured
151 50 측정하지 않음151 50 Not measured
152 30 측정하지 않음152 30 not measured
153 30 측정하지 않음153 30 does not measure
154 70 측정하지 않음154 70 Not measured
155 150 측정하지 않음 156 80 측정하지 않음155 150 Not measured 156 80 Not measured
157 120 측정하지 않음157 120 Not measured
158 40 측정하지 않음158 40 not measured
159 60 측정하지 않음159 60 not measured
160 25 측정하지 않음160 25 Not measured
161 40 측정하지 않음161 40 Not measured
162 50 측정하지 않음162 50 not measured
163 60 측정하지 않음163 60 not measured
164 70 측정하지 않음164 70 not measured
165 35 측정하지 않음165 35 not measured
166 60 측정하지 않음166 60 not measured
167 60 측정하지 않음167 60 not measured
168 40 측정하지 않음168 40 not measured
169 50 측정하지 않음169 50 Not measured
170 50 측정하지 않음170 50 Not measured
171 35 측정하지 않음171 35 not measured
172 40 측정하지 않음172 40 Not measured
173 65 측정하지 않음173 65 Not measured
174 65 측정하지 않음174 65 Not measured
175 60 측정하지 않음175 60 not measured
176 35 측정하지 않음176 35 not measured
177 40 측정하지 않음177 40 Not measured
178 35 측정하지 않음 179 70 측정하지 않음178 35 not measured 179 70 Not measured
180 40 측정하지 않음 180 40 Not measured
181 70 측정하지 않음  181 70 Not measured
182 70 측정하지 않음  182 70 not measured
183 60 측정하지 않음  183 60 not measured
184 60 측정하지 않음  184 60 not measured
상기 표 9에서 나타난 바와 같이, 본원 발명의 화합물은 비만 세포에서의 Syk 활성 저해 효과가 우수함을 알 수 있었다. As shown in Table 9, the compound of the present invention was found to be excellent in the Syk activity inhibitory effect in mast cells.
본 발명을 상기의 구체적인 실시예와 관련하여 기술하였지만， 첨부된 특허청구범위에 의해 정의된 본 발명의 범위 내에서 당 분야의 숙련자는 본 발명을 다양하게 변형 및 변화시킬 수 있다. Although the present invention has been described in connection with the specific embodiments described above, those skilled in the art can variously modify and change the present invention within the scope of the present invention as defined by the appended claims.

Claims

특허청구의 범위 Scope of Claim
1. 하기 화학식 (I)의 화합물， 및 약제학적으로 허용가능한 그의 염, 이성질체， 수화물 및 용매화물로 이루 : 1. A compound of formula (I) and pharmaceutically acceptable salts, isomers, hydrates and solvates thereof:
Figure imgf000135_0001
Figure imgf000135_0001
상기 식에서，  In the above formula,
W, X및 Y는 각각 독립적으로 C, N, 0또는 S이고, 이때， W, X및 Y중 하나 이상이 N인 경우 방향족 화합물을 구성할 수 있고， W, X 및 Y가 각각 C 또는 N인 경우， 치환기 R3을 가질 수 있고;  W, X and Y are each independently C, N, 0 or S, wherein at least one of W, X and Y is N may constitute an aromatic compound, W, X and Y are each C or N May have substituent R3;
O O  O O
A는 수소， 할로겐, 아미노카르보닐， 카르보닐아미노， ᅳ Cᅳ으， -0-C- , -0- ， 아미노， 우레아， 설포닐， 설폭시, '아미노설포닐 및 설포닐아미노로 이루어진 군에서 선택되고; A is hydrogen, halogen, aminocarbonyl, carbonylamino, ᅳ C ᅳ, -0-C-, -0-, amino, urea, sulfonyl, sulfoxy, ' aminosulfonyl and sulfonylamino Selected;
B는 수소， d-5 알킬， C2-s 알켄일 C5-12 아릴， C5-13 헤테로아릴， C3-13 사이클로알킬 또는 C3-13 해테로사이클로알킬이며, 여기에서 알킬， 알켄일， 아릴， 헤테로아릴， 사이클로알킬 및 헤테로사이클로알킬은 할로겐, d-5 알킬， 할로 알킬， C3-8사이클로알킬 , 하이드록시， C6-12아릴， d-5알콕시 , (d-5알콕시 )카르보닐 , 카르복실， 아미노， (c-5 알킬)아미노， 피페리딘일， 5 알콕시) -5 알킬, 모르포린일， 아미노카르보닐, 모르포린일 (c1-5 알킬)， (d-5 알킬)피페리딘일, (d-5 알콕시)카르보닐피페리딘일, 하이드톡시 (d-5 알킬), 하이드록시 (d-5 알콕시)， (C3-8 사이클로알킬 )(c1-5 알콕시)， C3-12 아릴옥시， 할로 (d-5 알킬) 및 할로 (C6-12 아릴)로 이루어진 군에서 선택되는 하나 이상의 치환기로 치환될 수 있고， (단, A가 수소 또는 할로겐인 경우 B는 존재하지 않으며); B is hydrogen, d- 5 alkyl, C 2 - s alkenyl, C 5 - 12 aryl, C 5 - 13 heteroaryl, C 3 - 13 cycloalkyl or C 3 - to 13 for interrogating and cycloalkyl, the alkyl here, Al alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is halogen, d- 5 alkyl, haloalkyl, C 3 - 8 cycloalkyl, hydroxy, C 6 - 12 aryl, 5 d- alkoxy, (d- 5 alkoxy ) Carbonyl, carboxyl, amino, (c- 5 alkyl) amino, piperidinyl, 5 alkoxy) -5 alkyl, morpholinyl, aminocarbonyl, morpholinyl (c 1-5 alkyl), (d- 5 alkyl) piperidinyl, (d- 5 alkoxy) carbonyl nilpi piperidinyl, hydroxy-ethoxy (5-d- alkyl), hydroxy (d- 5 alkoxy), (c 3 -8 cycloalkyl) (c 1-5 alkoxy), C 3 - 12 aryloxy, halo (d- 5 alkyl) and halo (C 6 - to 12 aryl group) may be substituted with one or more substituents selected from the group consisting of and, (where, a can Or when B is halogen is not present);
Rl, R2 및 R3는 각각 독립적으로 수소， 할로겐, 하이드록시， 아미노， d-s 알킬, C2-6 알켄일， C1-5 알콕시， d-5아미노， 아미노카보닐， 카보닐아미노， 설포닐，Rl, R2 and R3 are each independently hydrogen, halogen, hydroxy, amino, ds Alkyl, C 2 - 6 alkenyl, C 1-5 alkoxy, d- 5-amino, amino carbonyl, amino carbonyl, sulfonyl,
C5-12 아릴, C5-12 헤테로아릴， C5-12 바이사이클로아릴， C5-12 바이사이클로헤테로아릴，C 5 - 12 aryl, C 5 - 12 heteroaryl, C 5 - 12 bicyclo aryl, C 5 - 12 bicyclo heteroaryl,
C3-12 사이클로알킬 또는 C3-12 헤테로사이클로알킬이며， 여기에서， 알킬， 알켄일， 알콕시， 아미노， 아미노카보닐， 카보닐아미노， 설포닐 아릴， 헤테로아릴， 바이사이클로아릴 바이사이클로헤테로아릴 사이클로알킬 C 3 -12 cycloalkyl or C 3 - 12 and heterocycloalkyl, where the alkyl, alkenyl, alkoxy, amino, amino carbonyl, amino carbonyl, sulfonyl aryl, heteroaryl, aryl bicyclo bicyclo heteroaryl Cycloalkyl
헤테로사이클로알킬은 할로겐, 하이드록시， 아미노， d-5알킬, C1-5알콕시， d-5아민 설포닐， C5-12 아릴， C5-12 헤테로아릴， C5-12 바이사이클로아릴， C5-12 바이사이클로헤테로아릴， C3-12사이클로알킬 및 C3-]2헤테로사이클로알킬로 이루어진 군에서 선택되는 하나 이상의 치환기로 치환될 수 있다. Heterocycloalkyl, halogen, hydroxy, amino, d- 5 alkyl, C 1-5 alkoxy, d-amine 5-sulfonyl, C 5-12 aryl, C 5 - 12 heteroaryl, C 5 - 12 bicyclo aryl, C 5 - may be substituted with one or more substituents selected from - the group consisting of 2-heterocycloalkyl-bicyclo 12 heteroaryl, C 3 - 12 cycloalkyl, and C 3.
2. 제 1항에 있어서， 하기 화학식 (I-a)로 표시되는 화합물: 2. The compound according to claim 1, represented by the following formula (I-a):
Figure imgf000136_0001
상기 식에서 ,
Figure imgf000136_0001
Where
D는 C또는 N이고;  D is C or N;
Rl, R2 및 R3은 각각 독립적으로 수소， 할로겐， 하이드록시， 아미노， d-5 알킬， C2-<5 알켄일， d-5알콕시， d-5 아미노， 아미노카보닐， 카보닐아미노， 설포닐， C5-12아릴， C5-12바이사이클로아릴， C5-12바이사이클로헤테로아릴， C3-12사이클로알킬 또는 C3-12 헤테로사이클로알킬이고, 여기에서， 알킬， 알켄일， 알콕시， 아미노， 아미노카보닐， 카보닐아미노， 설포닐, 아릴, 바이사이클로아릴, 바이사이클로헤테로아릴， 사이클로알킬 및 헤테로사이클로알킬은 할로겐， 하이드록시， 아미노， d-5 알킬, C2-G 알켄일 알콕시， d-5 아민, 설포닐， C5-12 아릴， C5_12 헤테로아릴， C5-12바이사이클로아릴, C5-12바이사이클로헤테로아릴, C3-12 사이클로알킬 및 C3-12헤테로사이클로알킬로 이루어진 군에서 선택되는 하나 이상의 치환기로 치환될 수 있고; R1, R2 and R3 are each independently hydrogen, halogen, hydroxy, amino, d- 5 alkyl, C 2- <5 alkenyl, d- 5 alkoxy, d- 5 amino, aminocarbonyl, carbonylamino, sulf sulfonyl, C 5 - 12 aryl, C 5 - 12 bicyclo aryl, C 5 - 12 bicyclo heteroaryl, C 3 - 12 cycloalkyl or C 3 - 12, and heterocycloalkyl, where the alkyl, alkenyl, alkoxy , Amino, aminocarbonyl, carbonylamino, sulfonyl, aryl, bicycloaryl, bicycloheteroaryl, cycloalkyl and heterocycloalkyl are halogen, hydroxy, amino, d- 5 alkyl, C 2 -G alkenyl alkoxy, d- 5 amines, sulfonyl, C 5 - 12 aryl, C 5 _ 12 heteroaryl, C 5 - 12 bicyclo aryl, C 5 - 12 bicyclo heteroaryl, C 3 - 12 cycloalkyl, and C 3 - It is selected from the group consisting of 12 heterocycloalkyl Or more May be substituted with a substituent;
R4 및 R5는 각각 독립적으로 수소， d-5알킬， d-5알킬아미노， C2-6알켄일， C5-12아릴， C5-12바이사이클로아릴， ¾ᅳ12바이사이클로헤테로아릴， C3-12사이클로알킬 또는 C3-12 헤테로사이클로알킬이고, 여기에서, 알킬, 알킬아미노， 알켄일， 아릴, 바이사이클로아릴, 바이사이클로헤테로아릴， 사이클로알킬 및 헤테로사이클로알킬은 하이드록시, 아미노， 알킬아민， C 5알킬, C2-6알켄일， C5- 12아릴， C5— 12바이사이클로아릴， C5-12바이사이클로헤테로아릴, C3-12사이클로알킬 및 C3-12해테로사이클로알킬로 이루어진 군에서 선택되는 하나 이상의 치환기로 치환될 수 있고; R4 and R5 are each independently hydrogen, d- 5 alkyl, d- 5 alkylamino, C 2 - 6 alkenyl, C 5 - 12 aryl, C 5-12 bicyclo aryl, ¾ eu bicyclo 12 heteroaryl, C 3 - 12 cycloalkyl or C 3 - 12, and heterocycloalkyl, where the alkyl, amino, alkenyl, aryl, bicyclo aryl, bicyclo heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with hydroxy, amino, alkyl amine, C 5 alkyl, C 2 - 6 alkenyl, C 5 - 12 aryl, C 5 - 12 bicyclo aryl, C 5 - 12 bicyclo heteroaryl, C 3 - 12 cycloalkyl, and C 3 - 12 year Tero cycloalkyl May be substituted with one or more substituents selected from the group consisting of alkyl;
이때， R4 및 R5는 서로 연결되어 C3-6카보사이클， C2-6해테로사이클， C5—12 바이사이클 또는 C5-12헤테로바이사이클을 형성할 수 있으며, 여기에서 카보사이클， 헤테로사이클， 바이사이클 및 헤테로바이사이클은 할로겐， 하이드록시， 아미노， 알킬아민, 알킬， C2-6 알켄일， C5-12 아릴， C5-12 바이사이클로아릴， C5-12 바이사이클로헤테로아릴， C3-12사이클로알킬 및 C3-12헤테로사이클로알킬로 이루어진 군에서 선택되는 하나 이상의 치환기로 치환될 수 있고; In this case, R4 and R5 are connected to each other C 3-6 carbocycle, C 2 - 6 by interrogating cycle, C 5 - 12 by-cycle or C 5 - may form a 12-by-cycle heteroaryl, carbocycle Here, the heterocyclic cycle-by-cycle and heteroaryl-by-cycle is halogen, hydroxy, amino, alkyl amine, alkyl, C 2 - 6 alkenyl, C 5 - 12 aryl, C 5 - 12 bicyclo aryl, C 5 - 12 bicyclo heteroaryl , C 3 - 12 cycloalkyl, and C 3 - 12 may be substituted with heterocycloalkyl and one or more substituents selected from the group consisting of alkyl;
이때 R4 및 R5가 C2-G 헤테로사이클 또는 ¾ᅳ12 헤테로바이사이클인 경우, 헤테로 원소는 0， N, S, S=0 및 S02로 이루어진 군에서 선택되며， 헤테로 원소가 N인 경우 치환기 R6으로 치환될 수 있고， 이때, R6는 수소， d-3저급 알킬 또는 C3-6 사이클로알킬이고， 여기에서 저급 알킬 또는 사이클로 알킬은 하나 이상의 할로겐으로 치환될 수 있다. 제 1항에 있어서， 하기 화학식 (I-b)로 표시되는 화합물: Wherein when R4 and R5 are C 2 -G heterocycles or ¾ ᅳ 12 heterobicycles, the hetero element is selected from the group consisting of 0, N, S, S = 0 and S0 2 , and when the hetero element is N, a substituent can be optionally substituted with R6, wherein, R6 is hydrogen, d- 3 lower alkyl or C 3 - 6 may be substituted with cycloalkyl, lower alkyl or cycloalkyl substituted by one or more halogens here. The compound according to claim 1, represented by the following general formula (Ib):
Figure imgf000137_0001
(I-b) 상기 식에서 ,
Figure imgf000137_0001
(Ib) Where
X는 C 또는 N이고;  X is C or N;
R1은 수소; 할로겐; 및 하나 이상의 할로겐으로 임의로 치환된， C1-5알킬 및 d-5알콕시로 이루어진 군에서 선택되고; R 1 is hydrogen; halogen; And C 1-5 alkyl and d- 5 alkoxy, optionally substituted with one or more halogens;
R2는 수소; 할로겐; 및 하나 이상의 할로겐으로 임의로 치환된， 알킬， 알콕시 , ( 5아미노 및 C3-6사이클로알콕시로 이루어진 군에서 선택되며; R2 is hydrogen; halogen; And optionally substituted by one or more halogen, alkyl, alkoxy, (5-amino and C 3 - 6 are each individually selected from the group consisting of cycloalkoxy;
R3은 수소; 및 하나 이상의 할로겐으로 임의로 치환된, d-5 알킬 및 C3—12 사이클로알킬로 이루어진 군에서 선택되며; R3 is hydrogen; And d- 5 alkyl and C 3 — 12 cycloalkyl, optionally substituted with one or more halogens;
R4 및 R5는 각각 독립적으로 수소; 및 할로겐， 하이드록시, 아미노， 모폴린 피페리딘, 피페라진, 알킬피페라진 및 C3-6사이클로알킬피페라진으로 이루어진 군에서 선택되는 하나 이상의 치환기로 임의로 치환된， d-5알킬， 알킬아미노， C2-6 알켄일， C5-12 아릴, C5-12 바이사이클로아릴, C5-12 바이사이클로헤테로아릴， C3-12 사이클로알킬 및 _12헤테로사이클로알킬로 이루어진 군에서 선택되며; R4 and R5 are each independently hydrogen; And halogen, hydroxy, amino, morpholin-piperidine, piperazine, piperazine-alkyl and C 3 - 6 cycloalkyl, l l as the optionally substituted with one or more substituents selected from the group consisting of, d- 5 alkyl, amino , C 2 - 6 alkenyl, C 5 - 12 aryl, C 5 - 12 bicyclo aryl, C 5 - 12 bicyclo heteroaryl, C 3 - 12 cycloalkyl, and _ is selected from the group consisting of 12-heterocycloalkyl;
이때， R4 및 R5는 서로 연결되어 사이클을 형성할 수 있으며， 상기 사이클은 N, 0 및 S로 이루어진 군에서 선택된 하나 이상의 헤테로 원소를 포함할 수 있으며， 상기 헤테로 원소가 N인 경우 치환기 R6으로 치환될 수 있고, 이때， R6은 수소; 및 하나 이상의 할로겐으로 임의로 치환된, d-5알킬， C3-12사이클로알킬 및 C3-12사이클로알킬 -d-5알킬로 이루어진 군에서 선택될 수 있다. In this case, R4 and R5 may be connected to each other to form a cycle, the cycle may include one or more hetero elements selected from the group consisting of N, 0 and S, when the hetero element is N is substituted with a substituent R6 Wherein R 6 is hydrogen; And optionally substituted with one or more halogen, d- 5 alkyl, C 3 - 12 cycloalkyl can be selected from the group consisting of -d- alkyl 5 - 12 cycloalkyl, and C 3.
4. 제 1 항에 있어서， 하기 화학식 (I-c)로 표시되는 화합물: 4. A compound according to claim 1, represented by the formula (I-c):
Figure imgf000138_0001
상기 식에서 Rl은 수소; 할로겐; 및 하나 이상의 할로겐으로 임의로 치환된， d-5알킬 및 d-5알콕시로 이루어진 군에서 선택되고;
Figure imgf000138_0001
In the above formula Rl is hydrogen; halogen; And d- 5 alkyl and d- 5 alkoxy, optionally substituted with one or more halogens;
R2는 수소; 할로겐; 및 하나 이상의 할로겐으로 임의로 치환된， 알콕시 및 C3-G사이클로알콕시로 이루어진 군에서 선택되고; R2 is hydrogen; halogen; And alkoxy and C 3 -G cycloalkoxy, optionally substituted with one or more halogens;
R3은 수소; 및 하나 이상의 할로겐으로 임의로 치환된， 알킬 및 C3_12 사이클로알킬로 이루어진 군에서 선택되고; R3 is hydrogen; And C 3 _ 12 cycloalkyl, optionally substituted with one or more halogens;
R7 및 R8은 각각 독립적으로 수소; 및 하나 이상의 할로겐으로 임의로 치환된， 알킬 및 -12사이클로알킬로 이루어진 군에서 선택되고; R7 and R8 are each independently hydrogen; And alkyl and -12 cycloalkyl, optionally substituted with one or more halogens;
Z는 공유결합, -CHR6, -0-, -NR6- 및 -S02-로 이루어진 군에서 선택되고; 이때， 상기 R6은 하나 이상의 할로겐으 임의로 치환된， ( 5 알킬， C3—12 사이클로알킬 및 C3-12사이클로알킬 -d-s알킬로 이루어진 군에서 선택된다. Z is selected from the group consisting of a covalent bond, -CHR6, -0-, -NR6-, and -S0 2- ; Is selected from the group consisting of 12-cycloalkyl-alkyl -ds-In this case, the R6 is one or more halogen coming from optionally substituted, (5 alkyl, C 3 - 12 cycloalkyl, and C 3.
5. 제 1 항에 있어서， 하기 화학식 (I-d)로 표시되는 화합물:
Figure imgf000139_0001
5. The compound according to claim 1, represented by the following formula (Id):
Figure imgf000139_0001
상기 식에서,  Where
R1은 수소; 할로겐; 및 하나 이상의 할로겐으로 임의로 치환된， d-5알킬 및 ( 5알콕시로 이루어진 군에서 선랙되고; R 1 is hydrogen; halogen; And selected from the group consisting of d- 5 alkyl and 5 alkoxy, optionally substituted with one or more halogens;
R2는 수소; 할로겐; 및 하나 이상의 할로겐으로 임의로 치환된， C:-5 알콕시 및 C3-6사이클로알콕시로 이루어진 군에서 선택되고; R2 is hydrogen; halogen; And optionally substituted by one or more halogen, C: - 5 alkoxy and C 3 - 6 is selected from the group consisting of cycloalkoxy;
R3은 수소 ; 및 할로겐， d-5 알킬， 알콕시， C3-6 사이클로알콕시， d-6 알킬아미노， ¾-12사이클로알킬， C3-12헤테로사이클로알킬， C5-12아릴 및 C5-12헤테로 아릴로 이루어진 군에서 선택된 하나 이상의 치환기로 임의로 치환된, d-5알킬, ( 5 알콕시， C3-6사이클로알콕시 , 아미노， C1-6 알킬 아미노, -12사이클로알킬， C3-12 헤테로사이클로알킬， C5-12아릴 및 C5-12헤테로아릴로 이루어진 군에서 선택된다. R3 is hydrogen; And halogen, d- 5 alkyl, alkoxy, C 3 - to 12-heteroaryl-6 cycloalkoxy, d- 6 alkylamino, ¾ -12 cycloalkyl, C 3 - 12 heterocycloalkyl, C 5 - 12 aryl and C 5 optionally substituted with one or more substituents selected from the group consisting of, 5-d- alkyl, (5 alkoxy, C 3 - 6 cycloalkoxy, amino, C 1-6 alkylamino, - 12 cycloalkyl, C 3 - 12 heterocycloalkyl, C 5 - 12 aryl and is selected from the group consisting of C 5-12 heteroaryl.
6. 제 1 항에 있어서, 하기 화합물들로 이투어진 군으로부터 선택되는 것을 특징으로 하는， 화합물: 6. The compound according to item 1, which is selected from the group consisting of the following compounds:
1) 2-다이메틸아미노 -N-[2-메틸 -6ᅳ(8-메틸―퀴나졸린 -2-일아미노 )-1Η- 벤즈이미다졸 -4-일] -아세트아미드;  1) 2-dimethylamino-N- [2-methyl-6 ′ (8-methyl-quinazolin-2-ylamino) -1Η-benzimidazol-4-yl] -acetamide;
2) Nᅳ [2-메틸 -6-(8-메틸-퀴나졸린 -2—일아미노)— 1H-벤즈이미다졸 -4-일] -3- 피리딘 -3-일—프로피은아미드； 2) N '[2-methyl-6- (8-methyl-quinazolin-2-ylamino) —1H-benzimidazol-4-yl] -3-pyridin-3-yl—propynamide;
3) 모폴린 -4-카르복실산 [2-메틸 -6-(8-메틸-퀴나졸린 -2-일아미노)— 1H- 벤즈이미다졸 -4-일] -아미드；  3) morpholine-4-carboxylic acid [2-methyl-6- (8-methyl-quinazolin-2-ylamino) —1H-benzimidazol-4-yl] -amide;
4) 4-메틸-피페라진 -1-카르복실산 [2-메틸 -6-(8-메틸-퀴나졸린 -2-일아미노) - 1H-벤즈이미다졸 -4-일] -아미드; .  4) 4-Methyl-piperazine-1-carboxylic acid [2-methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -amide; .
5) N-[2-메틸 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4-일] -3- 피페리딘— 1-일 -프로피온아미드;  5) N- [2-Methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -3-piperidin— 1-yl-propionamide;
6) 1ᅳ[2-메틸 -6— (8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4-일] -3-(2- 모폴린—4—일—에틸) _우레아; 6) 1 ′ [2-Methyl-6— (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -3- (2-morpholine — 4 —yl—ethyl) Urea;
7) 1- ( 3-다이메틸아미노-프로필 ) -3- [ 2-메틸 -6- ( 8-메틸-퀴나졸린 -2-일아미노) - 1H-벤즈이미다졸 -4—일 ] -우레아； 7) 1- (3-dimethylamino-propyl) -3- [2-methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4—yl] -urea;
8) (2-메틸 -3H-벤즈이미다졸 -5-일 )-(8-메틸-퀴나졸린 -2-일 ) -아민；  8) (2-methyl-3H-benzimidazol-5-yl)-(8-methyl-quinazolin-2-yl) -amine;
9) (그브로모 -2—메틸 -3H-벤즈이미다졸 -5-일 )-(8-메틸-퀴나졸린 -2-일 ) -아민； 9) (Gbromo-2-methyl-3H-benzimidazol-5-yl)-(8-methyl-quinazolin-2-yl) -amine;
10) N— [2-메틸— 6-(8-메틸-퀴나졸린 -2-일아미노)ᅳ 1H-벤즈이미다졸 -4-일] -4ᅳ(4ᅳ 메틸-피페라진 -1-일) -부틸아미드; ' 10) N— [2-methyl- 6- (8-methyl-quinazolin-2-ylamino) '1H-benzimidazol-4-yl] -4' (4 'methyl-piperazin-1-yl) -Butylamide; '
11) [6ᅳ (7-브로모-퀴나졸린 -2-일아미노) -2-메틸 -1H-벤즈이미다졸ᅳ 4-일 ] - 카바민산에틸 에스터 ;  11) [6 ′ (7-Bromo-quinazolin-2-ylamino) -2-methyl-1H-benzimidazol-2-4-yl] -ethyl carbamate;
12) 1-(3-다이메틸아미노-프로필) 3ᅳ[6-(8—메틸ᅳ퀴나졸린 -2—일아미노) -1H- 인다졸—4-일] -우레아;  12) 1- (3-dimethylamino-propyl) 3 ′ [6- (8—methyl ᅳ quinazolin-2—ylamino) -1H-indazol—4-yl] -urea;
13) N6-(7-브로모-퀴나졸린 -2-일 ) -2-메틸— 1H-벤즈이미다졸 -4， 6-다이아민；13) N 6- (7-bromo-quinazolin-2-yl) -2-methyl—1H-benzimidazole-4, 6-diamine;
14) 4-(4-메틸-피페라진 -1-일) -N-[6ᅳ (8—메틸-퀴나졸린 -2-일아미노) -1H—인다졸- 4-일] -부틸아미드; 15) (7-브로모-퀴나졸린 -2ᅳ일 )-(2-메틸 -3H-벤즈이미다졸 -5—일 ) -아민； 14) 4- (4-methyl-piperazin-1-yl) -N- [6 ′ (8—methyl-quinazolin-2-ylamino) -1H—indazol-4-yl] -butylamide; 15) (7-bromo-quinazolin-2xyl)-(2-methyl-3H-benzimidazol-5-yl) -amine;
16) 2-메틸 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4-카르복실산 사이클로프로필아미드;  16) 2-methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazole-4-carboxylic acid cyclopropylamide;
17) 1— [2-메틸ᅳ 6-(8-메틸―퀴나졸린 -2-일아미노) -1H—벤즈이미다졸 -4-일 ]-3-(2- 피페리딘 -1-일-에틸) -우레아;  17) 1— [2-Methyl ᅳ 6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -3- (2-piperidin-1-yl-ethyl ) -Urea;
18) 피페리딘 -1-카르복실산 [2-메틸 -6-(8-메틸-퀴나졸린 -2-일아미노) -1Hᅳ 벤즈이미다졸 -4-일] -아미드；  18) piperidine-1-carboxylic acid [2-methyl-6- (8-methyl-quinazolin-2-ylamino) -1H′benzimidazol-4-yl] -amide;
19) 2-메틸— 6-(8-메틸 -퀴나졸린— 2-일아미노) -1H-벤즈이미다졸 -4-카르복실산 (2- 피페리딘 -1-일-에틸) -아미드;  19) 2-methyl- 6- (8-methyl-quinazolin- 2-ylamino) -1H-benzimidazole-4-carboxylic acid (2- piperidin-1-yl-ethyl) -amide;
20) [2-메틸 -6-(8-메틸 -퀴나졸린ᅳ 2-일아미노) -1H-벤즈이미다졸 4-일] -메탄을; 20) [2-methyl-6- (8-methyl-quinazolin 졸 2-ylamino) -1H-benzimidazol 4-yl] -methane;
21) 1-(3—다이메틸아미노-프로필) -1-메틸 -3-[2-메틸 -6-(8-메틸-퀴나졸린 -2- 일아미노) - 1H-벤즈이미다졸 -4-일] -우레아; 21) 1- (3—dimethylamino-propyl) -1-methyl-3- [2-methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl Urea;
22) 4-메틸 -피페라진ᅳ 1—카르복실산 [6-(8-메틸-퀴나졸린 -2-일아미노) -1H- 벤즈이미다졸 -4-일 ] -아미드;  22) 4-methyl-piperazinyl 1—carboxylic acid [6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -amide;
23) 피페리딘 -1-카르복실산 [ (8—메틸-퀴나졸린 -2-일아미노)ᅳ 1H-벤즈이미다졸- 4-일] -아미드;  23) piperidine-1-carboxylic acid [(8—methyl-quinazolin-2-ylamino) ᅳ 1H-benzimidazol-4-yl] -amide;
24) [2-메틸— 7-(3-피페리딘 -1—일-프로폭시메틸) -3H-벤즈이미다졸 -5-일] -(8- 메틸-퀴나졸린 -2-일)—아민;  24) [2-Methyl— 7- (3-piperidin-1—yl-propoxymethyl) -3H-benzimidazol-5-yl]-(8-methyl-quinazolin-2-yl) -amine ;
25) [2-사이클로프로필 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4- 일] -카바민산메틸 에스터 ;  25) [2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -methyl carbamate ester;
26) 1-(3-다이메틸아미노 -2， 2-다이메틸ᅳ프로필 )-3-[2-메틸 -6-(8-메틸-퀴나졸린- 2-일아미노) - 1H-벤즈이미다졸 -4—일；卜우레아;  26) 1- (3-Dimethylamino-2, 2-dimethyl ᅳ propyl) -3- [2-methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazole- 4—day; urea;
27) 1-[2ᅳ메틸 -6-(8-메틸-퀴나졸린 -2-일아미노) -1Hᅳ벤즈이미다졸 -4-일] -3-(3- 피를리딘 -1-일-프로필)—우레아;  27) 1- [2 ᅳ methyl-6- (8-methyl-quinazolin-2-ylamino) -1H ᅳ benzimidazol-4-yl] -3- (3-pyridin-1-yl-propyl ) —Urea;
28) 2—사이클로프로필 -NG— (8-메틸-퀴나졸린—2-일 )-1Η-벤즈이미다졸 -4， 6- 다이아민; 28) 2—cyclopropyl-N G — (8-methyl-quinazolin—2-yl) -1Η-benzimidazole-4, 6-diamine;
29) N6-(8-이소프로폭시 -퀴나졸린ᅳ2-일 )-2-메틸 -1H-벤즈이미다졸 -4， 6ᅳ다이아민； 30) l-(3-다이메틸아미노-프로필 )-3-[6-(8-메틸―퀴나졸린 -2-일아미노 )-1Η_ 벤즈이 미다졸 -4-일 ] -우레아; 29) N 6- (8-isopropoxy-quinazolin ᅳ 2-yl) -2-methyl-1H-benzimidazole-4, 6'diamine; 30) l- (3-dimethylamino-propyl) -3- [6- (8-methyl-quinazolin-2-ylamino) -1Η_ benzimidazol-4-yl] -urea;
31) 1-(3-다이메틸아미노-프로필 )-3-[6-(8-이소프로폭시-퀴나졸린 -2-일아미노) - 2-메틸 -1H-벤즈이 미 다졸 -4-일 ] -우레아；  31) 1- (3-Dimethylamino-propyl) -3- [6- (8-isopropoxy-quinazolin-2-ylamino)-2-methyl-1H-benzimidazol-4-yl]- Urea;
32) 4-메틸 -피페라진— 1-카르복실산 [6-(8-이소프로폭시 -퀴나졸린— 2-일아미노) - 2-메틸 -1H-벤즈이 미 다졸—4-일 ] -아미드 ;  32) 4-methyl-piperazine- 1-carboxylic acid [6- (8-isopropoxy-quinazolin- 2-ylamino)-2-methyl-1H-benzimidazol-4-yl] -amide;
33) N-[6-(8-이소프로폭시 -퀴나졸린 -2-일아미노) -2-메틸 -1H-벤즈이미다졸 -4ᅳ 일 ] -4-(4—메틸-피페라진— 1-일 )-부틸아미드 ;  33) N- [6- (8-isopropoxy-quinazolin-2-ylamino) -2-methyl-1H-benzimidazol-4xyl] -4- (4—methyl-piperazine— 1- Mono) -butylamide;
34) [2-사이클로프로필— 6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4ᅳ 일 ] -카바민산에틸 에스터 ;  34) [2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4xyl] -ethyl carbamate;
35) 피페라진 -1-일 -[2-(2-트리플루오로메틸 -3H-벤즈이미다졸 -5-일아미노) - 퀴나졸린-그일 ] -메탄온 ;  35) piperazin-1-yl-[2- (2-trifluoromethyl-3H-benzimidazol-5-ylamino) -quinazolin-gyl] -methanone;
36) 2-사이클로프로필 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이 미다졸 -4- 카르복실산 (2-피페리 딘 -1—일-에 틸 ) -아미드；  36) 2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1 H-benzimidazole-4-carboxylic acid (2-piperidin-1-yl-ethyl) -amide ;
37) 1- [2-사이클로프로필 -6-(8-메틸ᅳ퀴나졸린 -2—일아미 노) -1H—벤즈이 미다졸 -4- 일 ] -3- (3—다이메틸아미노-프로필 ) -우레아;  37) 1- [2-cyclopropyl-6- (8-methyl-quinazolin-2—ylamino) -1 H-benzimidazol-4-yl] -3- (3-dimethylamino-propyl)- Urea;
38) 4-메틸-피페라진 -1-카르복실산 [2-사이클로프로필— 6-(8-메틸-퀴나졸린 -2- 일아미노) -1H—벤즈이미다졸 -4-일 ]ᅳ아미드 ;  38) 4-methyl-piperazine-1-carboxylic acid [2-cyclopropyl— 6- (8-methyl-quinazolin-2-ylamino) -1H—benzimidazol-4-yl] ᅳ amide;
39) 4-이소프로필-피페라진 -1-카르복실산 [2-메틸— 6-(8-메 틸-퀴나졸린 -2- 일아미노 )-1Η-벤즈이 미다졸 -4-일 ] -아미드 ;  39) 4-isopropyl-piperazin-1-carboxylic acid [2-methyl- 6- (8-methyl-quinazolin-2-ylamino) -1Η-benzimidazol-4-yl] -amide;
40) 2-(2-사이클로프로필 -3H-벤즈이미다졸 -5—일아미노) -퀴나졸린 -7-카르복실산 메틸 에스터 ;  40) 2- (2-cyclopropyl-3H-benzimidazole-5-ylamino) -quinazolin-7-carboxylic acid methyl ester;
41) (4-메틸―피 페라진— 1-일 )-[2-(2-트리플루오로메틸 -3H-벤즈이 미다졸 -5- 일아미 노) -퀴나졸린 -그일 ] -메탄온；  41) (4-methyl-piperazin— 1-yl)-[2- (2-trifluoromethyl-3H-benzimidazol-5-ylamino) -quinazolin-gyl] -methanone;
42) 모폴린—4ᅳ카르복실산 [2-사이클로프로필 -6-(8-메틸-퀴나졸린 -2-일아미노) - 1H-벤즈이 미다졸 -4-일 ] -아미드；  42) morpholine—4′carboxylic acid [2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -amide;
43) 2-(2-사이클로프로필 -3H-벤즈이 미다졸 -5-일아미노) -퀴나졸린ᅳ 7-카르복실산 (2-모폴린 -4-일-에틸)—아미드; 43) 2- (2-cyclopropyl-3H-benzimidazol-5-ylamino) -quinazolin 나 7-carboxylic acid (2-morpholin-4-yl-ethyl) —amide;
44) 피를리딘 -2—카르복실산 [2-(2-트리플루오로메틸 -3H-벤즈이미다졸 -5- 일아미노)ᅳ퀴나졸린 -7-일] -아미드；  44) pyridine-2—carboxylic acid [2- (2-trifluoromethyl-3H-benzimidazol-5-aminoamino) quinquinazolin-7-yl] -amide;
45) N2-(2-트리폴루오로메틸— 3H-벤즈이미다졸 -5—일 ) -퀴나졸린 -2， 7-다이아민；45) N 2 - (2- tree pole to Luo methyl-3H- benzimidazol-5-yl) - quinazoline-2, 7-diamine;
46) [2-(4-메틸 -피페라진— 1-일) -3H-벤즈이미다졸 -5-일] -(8-메틸-퀴나졸린 -2ᅳ 일) -아민; 46) [2- (4-Methyl-piperazin—1-yl) -3H-benzimidazol-5-yl]-(8-methyl-quinazolin-2xyl) -amine;
47) (8ᅳ메틸-퀴나졸린 -2-일 )-(2-모폴린 -4ᅳ일 -3H-벤즈이미다졸 -5-일 ) -아민； 47) (8'methyl-quinazolin-2-yl)-(2-morpholine-4xyl-3H-benzimidazol-5-yl) -amine;
48) N5-(8-메틸-퀴나졸린—2—일 )-N2-(2-모폴린 -4-일-에틸 )-3H-벤즈이미다졸 -2， 5- 다이아민; 48) N 5 - (8- methyl-quinazolin-2-yl) -N 2 - (2- morpholin-4-yl-ethyl) -3H- benzimidazole-2, 5-diamine;
49) 모폴린 -4-카르복실산 [6-(8-이소프로폭시-퀴나졸린 -2-일아미노)— 2-메틸 -1H- 벤즈이미다졸一4-일] -아미드; " 49) morpholine-4-carboxylic acid [6- (8-isopropoxy-quinazolin-2-ylamino) — 2-methyl-1H-benzimidazol-1-4-yl] -amide; "
50) ( 8-이소프로폭시-퀴나졸린 -2-일) - ( 2-모폴린 -4-일ᅳ 3H-벤즈이미다졸ᅳ 5-일) - 아민;  50) (8-isopropoxy-quinazolin-2-yl)-(2-morpholin-4-yl ᅳ 3H-benzimidazol-5-yl)-amine;
51) 4-이소프로필—피페라진 -1-카르복실산 [6-(8-이소프로폭시—퀴나졸린 -2- 일아미노)— 2-메틸 -1H-벤즈이미다졸 -4-일] -아미드；  51) 4-isopropyl—piperazin-1-carboxylic acid [6- (8-isopropoxy—quinazolin-2-ylamino) — 2-methyl-1H-benzimidazol-4-yl] -amide ;
52) 2-(2-사이클로프로필 -3H-벤즈이미다졸 -5-일아미노) -퀴나졸린 -7-카르복실산 (2-피페리딘 -1-일-에틸) -아미드;  52) 2- (2-cyclopropyl-3H-benzimidazol-5-ylamino) -quinazolin-7-carboxylic acid (2-piperidin-1-yl-ethyl) -amide;
53) Νβ-(8-클로로-퀴나졸린 -2-일 )-2-메틸 -1Η-벤즈이미다졸 -4, 6-다이아민；53) N β- (8-chloro-quinazolin-2-yl) -2-methyl-1Η-benzimidazole-4, 6-diamine;
54) 4-메틸-피페라진 -1-카르복실산 [6-(8ᅳ클로로 -퀴나졸린ᅳ 2-일아미노) -2—메틸- 1H-벤즈이미다졸ᅳ 4—일] -아미드; 54) 4-methyl-piperazine-1-carboxylic acid [6- (8 ᅳ chloro-quinazolin 졸 2-ylamino) -2—methyl-1H-benzimidazol 4-yl] -amide;
55) 4-이소프로필-피페라진 -1-카르복실산 [6-(8-클로로-퀴나졸린 -2-일아미노) - 2-메틸 -1Η-벤즈이미다졸 -4-일] -아미드；  55) 4-isopropyl-piperazin-1-carboxylic acid [6- (8-chloro-quinazolin-2-ylamino)-2-methyl-1Η-benzimidazol-4-yl] -amide;
56) 4-이소프로필 -피페라진— 1-카르복실산 [2-사이클로프로필 -6-(8-메틸- 퀴나졸린 -2-일아미노) -1Η-벤즈이미다¾— 4-일] -아미드；  56) 4-Isopropyl-piperazin— 1-carboxylic acid [2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -l-benzimida¾- 4-yl] -amide ;
57) 모폴린 -4ᅳ카르복실산 [6-(8-클로로-퀴나졸린 -2-일아미노) -2-메틸 -1Η- 벤즈이미다졸—4-일] -아미드;  57) morpholine-4 ′ carboxylic acid [6- (8-chloro-quinazolin-2-ylamino) -2-methyl-1Η-benzimidazol—4-yl] -amide;
58) [2-(4-이소프로필―피페라진 -1—일 )-3Η-벤즈이미다졸 -5—일] -(8-메틸- 퀴나졸린 -2-일) -아민; 58) [2- (4-isopropyl-piperazine-1-yl) -3Η-benzimidazole-5-yl]-(8-methyl- Quinazolin-2-yl) -amine;
59) 피를리딘 -2-카르복실산 [2-(2ᅳ트리플루오로메틸 -3H-벤즈이미다졸 -5- 일아미노) -퀴나졸린 -8-일] -아미드；  59) pyridin-2-carboxylic acid [2- (2 ᅳ trifluoromethyl-3H-benzimidazole-5 ylamino) -quinazolin-8-yl] -amide;
60) 1—이소프로필—피페리딘 -4-카르복실산 [2-메틸 -6-(8-메틸ᅳ퀴나졸린 -2- 일아미노) -1H-벤즈이미다졸 -4-일] -아미드；  60) 1-isopropyl-piperidine-4-carboxylic acid [2-methyl-6- (8-methyl ᅳ quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -amide;
61) {2-[2-(4-이소프로필-피페라진 -1-일 )-3H-벤즈이미다졸 -5-일아미노] - 퀴나졸린 -7-일 }-(4-메틸-피페라진 -1-일 ) -메탄온；  61) {2- [2- (4-Isopropyl-piperazin-1-yl) -3H-benzimidazol-5-ylamino] -quinazolin-7-yl}-(4-methyl-piperazine- 1-day) -methanone;
62) 모폴린 -4-일 - [2— (2-트리플루오로메틸 -3H-벤즈이미다졸—5-일아미노) - 퀴나졸린 -7-일] -메탄온;  62) morpholin-4-yl- [2— (2-trifluoromethyl-3H-benzimidazol-5-ylamino) -quinazolin-7-yl] -methanone;
63) 1-이소프로필-피페리딘 -4-카르복실산 [2-사이클로프로필 -6ᅳ (8- 이소프로폭시 -퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4-일]—아미드；  63) 1-isopropyl-piperidine-4-carboxylic acid [2-cyclopropyl-6 ′ (8-isopropoxy-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -amides;
64) 모폴린 -4-카르복실산 [2-사이클로프로필— 6-(8-이소프로폭시ᅳ퀴나졸린 -2- 일아미노) -1H-벤즈이미다졸 -4ᅳ일] -아미드;  64) morpholine-4-carboxylic acid [2-cyclopropyl— 6- (8-isopropoxy 폭 quinazolin-2-ylamino) -1H-benzimidazol-4xyl] -amide;
65) 1-이소프로필-피페리딘 -4-카르복실산 [6-(8ᅳ클로로-퀴나졸린 -2-일아미노) - 2-메틸 -1H-벤즈이미다졸 -4-일] -아미드；  65) 1-isopropyl-piperidine-4-carboxylic acid [6- (8 ᅳ chloro-quinazolin-2-ylamino)-2-methyl-1H-benzimidazol-4-yl] -amide;
66) 모폴린 -4-카르복실산 [2-메틸 -6-(8-트리플루오로메틸-퀴나졸린 -2- 일아미노) - 1H-벤즈이미다졸 -4-일] -아미드;  66) morpholine-4-carboxylic acid [2-methyl-6- (8-trifluoromethyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -amide;
67) 1-이소프로필ᅳ피페리딘 -4-카르복실산 [6-(8-이소프로폭시-퀴나졸린 -2- 일아미노 )-2ᅳ메틸 -1Hᅳ벤즈이미다졸 -4-일] -아미드；  67) 1-isopropyl ᅳ piperidine-4-carboxylic acid [6- (8-isopropoxy-quinazolin-2-ylamino) -2 ᅳ methyl-1H ᅳ benzimidazol-4-yl]- amides;
68) 4-이소프로필ᅳ피페라진 -1-카르복실산 [2-메틸 -6— (8-트리플루오로메틸- 퀴나졸린 -2-일아미노) -1Hᅳ벤즈이미다졸ᅳ 4-일 ] -아미드；  68) 4-isopropyl ᅳ piperazin-1-carboxylic acid [2-methyl-6— (8-trifluoromethyl-quinazolin-2-ylamino) -1H ᅳ benzimidazol ᅳ 4-yl]- amides;
69) 4-(1-하이드록시 -1-메틸-에틸) -피페리딘 -1-카르복실산 [2-메틸— 6-(8ᅳ메틸- 퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4-일] -아미드； ' 69) 4- (1-hydroxy-1-methyl-ethyl) -piperidine-1-carboxylic acid [2-methyl- 6- (8-methyl-quinazolin-2-ylamino) -1H-benz Imidazol-4-yl] -amide; '
70) 테트라하이드로 -피란 -4-카르복실산 [2-메틸 -6-(8-메틸-퀴나졸린 -2- 일아미노) -1H-벤즈이미다졸 -4ᅳ일]—아미드；  70) tetrahydro-pyran-4-carboxylic acid [2-methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4xyl] —amide;
71) {2-[2-(4-이소프로필 -피페라진— 1-일) -3H-벤즈이미다졸 -5-일아미노] - 퀴나졸린 -7-일 }-모폴린 -4-일-메탄온； 72) 테트라하이드로 -퓨란 -3-카르복실산 [2-메틸 -6ᅳ (8ᅳ메틸-퀴나졸린 -2- 일아미노 )-1Η-벤즈이 미다졸 -4-일 ] -아미드； 71) {2- [2- (4-isopropyl-piperazin— 1-yl) -3H-benzimidazol-5-ylamino] -quinazolin-7-yl} -morpholine-4-yl-methane On; 72) tetrahydro-furan-3-carboxylic acid [2-methyl-6 ′ (8′methyl-quinazolin-2-ylamino) -1Η-benzimidazol-4-yl] -amide;
73) 4-메틸-테트라하이드로 -피 란 -4-카르복실산 [2-메틸ᅳ 6-(8-메틸-퀴나졸린 -2- 일아미노)ᅳ 1H-벤즈이 미다졸 -4-일 ] -아미드；  73) 4-Methyl-tetrahydro-pyran-4-carboxylic acid [2-methyl ᅳ 6- (8-methyl-quinazolin-2-ylamino) ᅳ 1H-benzimidazol-4-yl] -amide ;
74) 2， 6—다이메틸-모폴린 -4-카르복실산 [2—메틸 -6-(8-메틸-퀴나졸린 -2- 일아미노) -1H-벤즈이 미다졸— 4-일 ] -아미드；  74) 2, 6-Dimethyl-morpholine-4-carboxylic acid [2—methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol- 4-yl] -amide ;
75) 모폴린 -4-일 - [ 2- ( 2-모폴린 -4-일 -3H—벤즈이 미다졸 -5-일아미노) -퀴나졸린 -7- 일 ] -메탄은 ;  75) morpholin-4-yl- [2- (2-morpholin-4-yl-3H—benzimidazol-5-ylamino) -quinazolin-7-yl] -methane is;
76) [2-사이클로프로필 -6-(8-메틸-퀴나졸린—2-일아미 노) -1H-벤즈이미다졸 -4- 일 ] -모플린 -4-일-메탄온 ;  76) [2-cyclopropyl-6- (8-methyl-quinazolin—2-ylamino) -1H-benzimidazol-4-yl] -morpholin-4-yl-methanone;
77) 테트라하이드로 -피 란 -4-카르복실산 [2-사이클로프로필 -6-(8-메틸ᅳ퀴나졸린- 2-일아미노) -1H-벤즈이미다졸— 4ᅳ일 ] -아미드；  77) tetrahydro-pyran-4-carboxylic acid [2-cyclopropyl-6- (8-methyl ᅳ quinazolin-2-ylamino) -1H-benzimidazol—4 quinyl] -amide;
78) N-[2-사이클로프로필 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이 미 다졸 -4- 일 ] -2-모폴린 -4-일-아세트아미드 ;  78) N- [2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -2-morpholin-4-yl-acetamide;
79) 5-[2-(2-메틸 -3H-벤즈이미 다졸 -5-일아미노) -퀴나졸린—7-일옥시 메틸 ] - 옥사졸리딘 -2-온 ;  79) 5- [2- (2-methyl-3H-benzimidazol-5-ylamino) -quinazolin-7-yloxy methyl] -oxazolidin-2-one;
80) 4-메틸 -테트라하이드로—피 란 -4-카르복실산 [2-사이클로프로필 -6-(8-메틸- 퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4-일 ]ᅳ아미드；  80) 4-Methyl-tetrahydro-pyran-4-carboxylic acid [2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] ᅳ amides;
81) 4-(2，2，2-트리플루오로-에 틸 ) -피페라진 -1-카르복실산 [2-사이클로프로필 -6- (8-메틸-퀴나졸린ᅳ2ᅳ일아미노) -1H-벤즈이미다졸 -4-일 ] -아미드；  81) 4- (2,2,2-trifluoro-ethyl) -piperazine-1-carboxylic acid [2-cyclopropyl-6- (8-methyl-quinazolin ᅳ 2 ᅳ ylamino) -1H- Benzimidazol-4-yl] -amide;
82) (7-클로로ᅳ2-사이클로프로필 -3-메틸 -3H-벤즈이 미다졸 -5-일 )-(8-메 틸- 퀴나졸린 -2一일 ) -아민 ;  82) (7-chloro- 2-cyclopropyl-3-methyl-3H-benzimidazol-5-yl)-(8-methyl-quinazolin-2yyl) -amine;
83) 1-[2-메틸ᅳ 6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이 미 다졸 4-일 ] -3-(4- 모폴린 -4-일-페닐 ) -우레아 ;  83) 1- [2-Methyl ᅳ 6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol 4-yl] -3- (4-morpholin-4-yl-phenyl)- Urea;
84) N-[2—메틸ᅳ 6-(8-메틸-퀴나졸린 -2-일아미노 )-1Η-벤즈이 미다졸 -4—일 ] -4- 모폴린 -4-일-벤즈아미드 ;  84) N- [2—methyl ᅳ 6- (8-methyl-quinazolin-2-ylamino) -1Η-benzimidazol-4—yl] -4-morpholin-4-yl-benzamide;
85) N-[2-사이클로프로필 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이 미다졸 -4- 일] -4-모풀린 -4-일―벤즈아미드； 85) N- [2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazole-4- General] -4-morpholin-4-yl-benzamide;
86) 3-플루오로 -N-[2-메틸 -6ᅳ(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4- 일 ]—5-모폴린 -4-일-벤즈아미드；  86) 3-fluoro-N- [2-methyl-6 ′ (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] —5-morpholin-4-yl- Benzamide;
87) N-[2-사이클로프로필ᅳ 6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 4ᅳ 일] -3-폴루오로 -5-모폴린 -4-일-벤즈아미드;  87) N- [2-cyclopropyl ᅳ 6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol 4xyl] -3-polouro-5-morpholin-4-yl Benzamide;
88) 모폴린 -4ᅳ설폰산 [2-사이클로프로필ᅳ6-(8ᅳ메틸 -퀴나졸린— 2-일아미노) -1H- 벤즈이미다졸 -4-일 ] -아미드；  88) morpholine-4'sulfonic acid [2-cyclopropyl'6- (8'methyl-quinazolin- 2-ylamino) -1H-benzimidazol-4-yl] -amide;
89) 1-[2-사이클로프로필 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4- 일] -3-(3-모폴린 -4-일-페닐) -우레아;  89) 1- [2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -3- (3-morpholin-4-yl-phenyl ) -Urea;
90) N— [2-메틸 -6-(8-메틸-퀴나졸린 -2-일아미노)— 1H-벤즈이미다졸 -4-일] - 니코틴아미드;  90) N— [2-methyl-6- (8-methyl-quinazolin-2-ylamino) — 1H-benzimidazol-4-yl] -nicotinamide;
91) 1-[2-메틸 -6-(8-메틸—퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4-일 ]-3ᅳ(3- 모폴린 -4-일ᅳ페닐) -우레아;  91) 1- [2-methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -3 '(3-morpholine-4-yl ᅳ phenyl) Urea;
92) [7-(1-메틸-피페리딘 -4-일옥시 ) -퀴나졸린 -2-일] -(2-^리플루오로메틸ᅳ 3H- 벤즈이미다졸 -5-일) -아민;  92) [7- (1-Methyl-piperidin-4-yloxy) -quinazolin-2-yl]-(2- ^ rifluoromethyl '3H-benzimidazol-5-yl) -amine;
93) N-[2-사이클로프로필 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4- 일] -니코틴아미드;  93) N- [2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -nicotinamide;
94) 2—사이클로프로필 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4- 카르복실산 (4-모폴린 -4-일ᅳ페닐) -아미드;  94) 2—cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazole-4-carboxylic acid (4-morpholin-4-yl ᅳ phenyl) -amide;
95) N-[2-사이클로프로필 -6— (8-메틸-퀴나졸린 -2-일아미노)— 1H-벤즈이미다졸 -4- 일] -4—모폴린 -4-일메틸-벤즈아미드;  95) N- [2-cyclopropyl-6— (8-methyl-quinazolin-2-ylamino) —1H-benzimidazol-4-yl] -4—morpholin-4-ylmethyl-benzamide;
96) N-[2ᅳ사이클로프로필 -6-(8-메틸 -퀴나졸린— 2-일아미노) -1H-벤즈이미다졸 -4- 일]— 4ᅳ (4-메틸-피페라진 -1-일 ) -벤즈아미드；  96) N- [2′cyclopropyl-6- (8-methyl-quinazolin—2-ylamino) -1H-benzimidazol-4-yl] — 4 ′ (4-methyl-piperazin-1-yl ) -Benzamide;
97) 모폴린 -4-카르복실산 [2-사이클로프로필 -1-메틸— 6ᅳ(8-메틸-퀴나졸린 -2- 일아미노) -1H-벤즈이미다졸 -4-일] -아미드；  97) morpholine-4-carboxylic acid [2-cyclopropyl-1-methyl- 6 ′ (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -amide;
98) 2-사이클로프로필 -6-(8-메틸―퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4- 카르복실산 [4-(4-메틸-피페라진 -1-일 ) -페닐] -아미드； 99) 2-사이클로프로필 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이 미다졸— 4- 카르복실산 (4-모폴린 -4-일메틸-페닐 ) -아미드； 98) 2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazole-4-carboxylic acid [4- (4-methyl-piperazin-1-yl)- Phenyl] -amide; 99) 2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazole— 4-carboxylic acid (4-morpholin-4-ylmethyl-phenyl) -amide;
100) N-[2-사이클로프로필 -6-(8-메틸-퀴나졸린 -2ᅳ일아미 노) -1H-벤즈이 미 다졸 -4- 일 ] -3-(4-메틸-피 페라진— 1-일메틸 ) -벤즈아미드；  100) N- [2-cyclopropyl-6- (8-methyl-quinazolin-2 boylamimino) -1 H-benzimidazol-4-yl] -3- (4-methyl-piperazine— 1- Monomethyl) -benzamide;
101) 2 , 6-다이 메틸-모폴린 -4-카르복실산 [2-사이클로프로필 -6-(8-메틸-퀴나졸린- 2-일아미노) -1H-벤즈이 미다졸 -4-일 ] -아미드； .  101) 2,6-dimethyl-morpholine-4-carboxylic acid [2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl]- Amide;
102) 모폴린 -4-카르복실산 [2-이소프로필 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H- 벤즈이 미다졸 -4-일 ]ᅳ아미드；  102) morpholine-4-carboxylic acid [2-isopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] ᅳ amide;
103) 1- [ 2-사이클로프로필 -6- ( 8-메틸-퀴나졸린—2-일아미노) -1H-벤즈이 미 다졸 -4- 일 ]— 3-(4-모폴린 -4-일-페닐 ) -우레아 ;  103) 1- [2-cyclopropyl-6- (8-methyl-quinazolin—2-ylamino) -1H-benzimidazol-4-yl] — 3- (4-morpholin-4-yl-phenyl ) -Urea;
104) 4-메 틸-피페라진 -1-카르복실산 [2-사이클로프로필 -1-메틸 -6-(8-메틸- 퀴나졸린 -2-일아미노 )-1Η-벤즈이 미다졸 -4-일 ] -아미드；  104) 4-Methyl-piperazin-1-carboxylic acid [2-cyclopropyl-1-methyl-6- (8-methyl-quinazolin-2-ylamino) -1Η-benzimidazol-4-yl ] -Amide;
105) 2-사이클로프로필 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이 미다졸 -4- 카르복실산 (3-모폴린 -4-일-페닐 ) -아미드 ;  105) 2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazole-4-carboxylic acid (3-morpholin-4-yl-phenyl) -amide;
106) N-[2-이소프로필 -6ᅳ(8-메틸-퀴 나졸린 -2-일아미노) -1H-벤즈이 미다졸 -4ᅳ일 ] - 4-모폴린 -4-일-벤즈아미드 ;  106) N- [2-isopropyl-6 ′ (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4xyl] -4-morpholin-4-yl-benzamide;
107) N— [2—이소프로필 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이 미다졸ᅳ 4ᅳ일 ] - 3_(4_메틸-피페라진 _卜일메틸 ) -벤즈아미드； 107) N— [2—isopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazolazinylxyl] -3 _ ( 4 _methyl-piperazin _xylmethyl) -Benzamide;
108) 2-사이클로프로필— 6— (8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이 미다졸 -4- 카르복실산 [3-(4-메틸―피페라진 -1-일메틸 ) -페닐 ] -아미드； 108) 2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazole-4-carboxylic acid [3- (4-methyl-piperazin-1-ylmethyl) -Phenyl] -amide;
109) 2-사이클로프로필 -6-(8-메틸 -퀴나졸린ᅳ 2-일아미노) -1H-벤즈이미다졸 -4- 카르복실산 [3-(4-메틸-피 페라진 -1-일；卜페 닐 ] -아미드；  109) 2-cyclopropyl-6- (8-methyl-quinazolinolin 2-ylamino) -1H-benzimidazole-4-carboxylic acid [3- (4-methyl-piperazin-1-yl; Champenyl] -amide;
110) 6-(8-메틸-퀴 나졸린 -2-일아미노) -1H-벤조트리아졸 -4-카르복실산 (4-모폴린- 4ᅳ일-페닐 ) -아미드 ;  110) 6- (8-methyl-quinazolin-2-ylamino) -1H-benzotriazole-4-carboxylic acid (4-morpholine-4 ylyl-phenyl) -amide;
111) 1-[2-이소프로필— 6-(8-메틸-퀴 나졸린 -2-일아미노) -1H—벤즈이 미다졸 -4-일 ] - 3ᅳ (4—모폴린 -4-일-페닐 )—우레아; 111) 1- [2-isopropyl— 6- (8-methyl-quinazolin-2-ylamino) -1H—benzimidazol-4-yl] -3 ′ (4—morpholin-4-yl- Phenyl) —urea;
112) 2-메틸— 6-(8-메틸-퀴나졸린 -2-일아미 노) -1H-벤즈이 미다졸ᅳ 4-카르복실산 (4- 모폴린 -4—일-페닐) -아미드; 112) 2-Methyl— 6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-carboxylic acid (4- Morpholine-4-yl-phenyl) -amide;
113) N-[2-사이클로프로필 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4- 일] -3— (4-메틸-피페라진 -1-일 ) -벤즈아미드；  113) N- [2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -3— (4-methyl-piperazin-1-yl ) -Benzamide;
114) 1-[2-사이클로프로필 -1-메틸 -6— (8-메틸-퀴나졸린 -2ᅳ일아미노) -1H- 벤즈이미다졸 -4-일] -3— (4-모폴린 -4—일-페닐)—우레아;  114) 1- [2-cyclopropyl-1-methyl-6— (8-methyl-quinazolin-2xylamino) -1H-benzimidazol-4-yl] -3— (4-morpholine-4— Phenyl) —urea;
115) 2-메틸 -6ᅳ(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4-카르복실산 (4- 모폴린 -4-일메틸-페닐) -아미드;  115) 2-Methyl-6 '(8-methyl-quinazolin-2-ylamino) -1H-benzimidazole-4-carboxylic acid (4-morpholine-4-ylmethyl-phenyl) -amide;
116) 2-이소프로필 -6-(8—메틸-퀴나졸린 -2-일아미노)ᅳ 1H—벤즈이미다졸 -4- 카르복실산 (4-모폴린 -4-일-페닐) -아미드;  116) 2-isopropyl-6- (8-methyl-quinazolin-2-ylamino) '1H-benzimidazole-4-carboxylic acid (4-morpholin-4-yl-phenyl) -amide;
117) 2-사이클로프로필 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4- 카르복실산 (3-모폴린 -4—일메틸-페닐 ) -아미드；  117) 2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazole-4-carboxylic acid (3-morpholine-4—ylmethyl-phenyl) -amide;
118) 2-사이클로프로필 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H—벤즈이미다졸 -4- 카르복실산 [4-(4-이소프로필-피페라진— 1-일메틸 ) -페닐 ] -아미드；  118) 2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H—benzimidazole-4-carboxylic acid [4- (4-isopropyl-piperazin— 1-ylmethyl ) -Phenyl] -amide;
119) [2-사이클로프로필 -6-(8-메틸―퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4ᅳ 일] -[4-(2 , 2 , 2-트리플루오로-에틸 ) -피페라진 -1-일] -메탄온；  119) [2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4xyl]-[4- (2, 2, 2-trifluoro-ethyl ) -Piperazin-1-yl] -methanone;
120) 2-사이클로프로필 -6— (8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4- 카르복실산 (6-모폴린 -4-일-피리딘— 3-일 ) -아미드;  120) 2-cyclopropyl-6— (8-methyl-quinazolin-2-ylamino) -1H-benzimidazole-4-carboxylic acid (6-morpholin-4-yl-pyridine— 3-yl) -amides;
121) 2-이소프로필 -6— (8-메틸-퀴나졸린—2-알아미노) -1H—벤즈이미다졸 -4- 카르복실산 (3-모폴린 -4-일메틸-페닐) -아미드;  121) 2-isopropyl-6- (8-methyl-quinazolin—2-alamino) -1H-benzimidazole-4-carboxylic acid (3-morpholine-4-ylmethyl-phenyl) -amide;
122) 2—메틸 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4-카르복실산 (3- 모폴린 -4-일메틸-페닐 ) -아미드；  122) 2-methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazole-4-carboxylic acid (3- morpholin-4-ylmethyl-phenyl) -amide;
123) 모폴린 -4-카르복실산 [1,2-다이메틸 -6-(8-메틸 -퀴나졸린ᅳ 2-일아미노) -1H- 벤즈이미다졸 -4-일] -아미드;.  123) morpholine-4-carboxylic acid [1,2-dimethyl-6- (8-methyl-quinazolinyl 2-ylamino) -1H-benzimidazol-4-yl] -amide;
124) [2-사이클로프로필 -1-메틸 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H- 벤즈이미다졸—4—일] -메틸-카바민산에틸 에스터;  124) [2-cyclopropyl-1-methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol—4—yl] -methyl-carbamate ethyl ester;
125) [ 1，4 ' ]Bi피페리딘일 -1 '-일 -[2-메틸 -6— (8-메틸-퀴나졸린 -2—일아미노) -1H- 벤즈이미다졸 -4—일] -메탄온; 126) 모폴린 -4-카르복실산 [6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤조트리아졸 -4- 일] -아미드; 125) [1,4 ′] Bipiperidinyl-1′-yl- [2-methyl-6— (8-methyl-quinazolin-2—ylamino) -1H-benzimidazole-4—yl]- Methanone; 126) morpholine-4-carboxylic acid [6- (8-methyl-quinazolin-2-ylamino) -1H-benzotriazol-4-yl] -amide;
127) N-[ 1 ,2-다이메틸 -6-(8-메틸―퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4-일] - 4-모폴린 -4ᅳ일메틸-벤즈아미드；  127) N- [1,2-dimethyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -4 morpholine- 4-monylmethyl-benzamide ;
128) 4-메틸ᅳ피페라진 -1-카르복실산 [1，2-다이메틸 -6-(8-메틸-퀴나졸린 -2- 일아미노) -1H-벤즈이미다졸 -4-일] -아미드；  128) 4-Methylcopiperazine-1-carboxylic acid [1,2-dimethyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -amide ;
129) 모폴린 -4-카르복실산 [1-에틸ᅳ 2—메틸 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H- 벤즈이미다졸 -4-일] -아미드;  129) morpholine-4-carboxylic acid [1-ethyl ᅳ 2-methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -amide;
130) 모폴린 -4-카르복실산 [2-사이클로프로필 -6-(8—메틸-퀴나졸린 -2-일아미노) - 1H-벤즈이미다졸ᅳ 4-일] -메틸 -아미드；  130) morpholine-4-carboxylic acid [2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -methyl-amide;
131) 모폴린 -4-카르복실산 [2-사이클로프로필 -1-메틸 -6-(8-메틸-뷔나졸린 -2- 일아미노) -1H-벤즈이미다졸 -4-일]ᅳ메틸ᅳ아미드；  131) morpholine-4-carboxylic acid [2-cyclopropyl-1-methyl-6- (8-methyl-vinazolin-2-ylamino) -1H-benzimidazol-4-yl] ᅳ methyl ᅳ amide ;
132) 4-이소프로필-피페라진 -1-카르복실산 [1，2ᅳ하이메틸 -6-(8-메틸-퀴나졸린 -2- 일아미노) -1H-벤즈이미다졸 -4-일 ]ᅳ아미드；  132) 4-isopropyl-piperazine-1-carboxylic acid [1,2 'hydroxy-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] ᅳ amides;
133) N-[l-에틸 -2—메틸 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4-일] - 4-모폴린 -4-일메틸-벤즈아미드；  133) N- [l-ethyl-2-methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl]-4-morpholin-4-ylmethyl- Benzamide;
134) 4-메틸-피페라진 -1-카르복실산 [1-에틸 -2-메틸 -6-(8-메틸-퀴나졸린 -2- 일아미노) -1H-벤즈이미다졸 -4—일]ᅳ아미드;  134) 4-Methyl-piperazine-1-carboxylic acid [1-ethyl-2-methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazole-4—yl] ᅳ amides;
135) 모폴린 -4-카르복실산 [2-사이클로프로필 -1-에틸 -6-(8-메틸-퀴나졸린 -2- 일아미노) -1H-벤즈이미다졸 -4-일] -아미드；  135) morpholine-4-carboxylic acid [2-cyclopropyl-1-ethyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -amide;
136) 4-메틸-피페라진 -1-카르복실산 [2-사이클로프로필 -1-에틸 -6-(8-메틸- 퀴나졸린 -2ᅳ일아미노) -1H-벤즈이미다졸 -4-일] -아미드；  136) 4-Methyl-piperazine-1-carboxylic acid [2-cyclopropyl-1-ethyl-6- (8-methyl-quinazolin-2xylamino) -1H-benzimidazol-4-yl]- amides;
137) 4-이소프로필-피페라진 -1-카르복실산 [2-사이클로프로필 -1-에틸 -6-(8—메틸- 퀴나졸린—2ᅳ일아미노) -1H-벤즈이미다졸 -4-일]ᅳ아미드；  137) 4-isopropyl-piperazine-1-carboxylic acid [2-cyclopropyl-1-ethyl-6- (8—methyl-quinazolin—2xylamino) -1H-benzimidazol-4-yl] Amide;
138) 2-사이클로프로필 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H—벤즈이미다졸—4- - 카르복실산 ( 1-이소프로필-피페리딘— 4-일 ) -아미드；  138) 2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -lH-benzimidazole-4- -carboxylic acid (1-isopropyl-piperidine- 4-yl)- amides;
139) 테트라하이드로 -피란 -4-카르복실산 [2-사이클로프로필— 1-에틸 -6-(8-메틸- 퀴나졸린 -2-일아미노)— 1H-벤즈이미다졸 -4-일] -아미드； 139) tetrahydro-pyran-4-carboxylic acid [2-cyclopropyl— 1-ethyl-6- (8-methyl- Quinazolin-2-ylamino) —1H-benzimidazol-4-yl] -amide;
140) N— [ 1-에틸 -2-메틸 -6- (8-메틸-퀴나졸린 -2-일아미노) -1Hᅳ벤즈이미다졸— 4-일] - 2-모폴린 -4-일-아세트아미드;  140) N— [1-ethyl-2-methyl-6- (8-methyl-quinazolin-2-ylamino) -1H ᅳ benzimidazol— 4-yl]-2-morpholin-4-yl-acet amides;
141) 테트라하이드로 -피란 -4-카르복실산 [1-에틸 -2-메틸 -6-(8-메틸-퀴나졸린 -2- 일아미노) -1H-벤즈이미다졸 -4-일] -아미드;  141) tetrahydro-pyran-4-carboxylic acid [1-ethyl-2-methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -amide;
142) N-[2-사이클로프로필 -1-에틸 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H- 벤즈이미다졸 -4-일] -2-모폴린 -4-일 -아세트아미드；  142) N- [2-cyclopropyl-1-ethyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -2-morpholin-4-yl- Acetamide;
143) N-[2-사이클로프로필— 1-에틸 -6-(8-메틸 -퀴나졸린ᅳ 2-일아미노) -1H- 벤즈이미다졸 -4-일] -2-다이메틸아미노-아세트아미드;  143) N- [2-cyclopropyl—l-ethyl-6- (8-methyl-quinazolinyl 2-ylamino) -1H-benzimidazol-4-yl] -2-dimethylamino-acetamide;
144) 2，6-다이메틸-모폴린 -4-카르복실산 [2-사이클로프로필 -1-에틸 -6-(8-메틸- 퀴나졸린 -2-일아미노)ᅳ 1H-벤즈이미다졸ᅳ 4—일]—아미드;  144) 2,6-dimethyl-morpholine-4-carboxylic acid [2-cyclopropyl-1-ethyl-6- (8-methyl-quinazolin-2-ylamino) '1H-benzimidazol ᅳ 4 —Work] —amide;
145) 4-이소프로필-피페라진 -1-카르복실산 [1-에틸 -2-메틸ᅳ 6-(8ᅳ메틸-퀴나졸린- 2-일아미노) -1H-벤즈이미다졸 -4-일] -아미드；  145) 4-isopropyl-piperazine-1-carboxylic acid [1-ethyl-2-methyl 6- (8 ᅳ methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -amides;
146) [2-사이클로프로필— 6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4- 일] -(4-이소프로필—피페라진 -1-일) -메탄온;  146) [2-cyclopropyl— 6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl]-(4-isopropyl-piperazin-1-yl) -methane On;
147) [2ᅳ메틸 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 4-일] -(4- 모폴린 -4-일-피페리딘 -1-일 ) -메탄온；  147) [2′methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol 4-yl]-(4-morpholin-4-yl-piperidin-1-yl ) -Methanone;
148) [2ᅳ사이클로프로필 -6-(8-메틸―퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4— 일] -(4-모폴린 -4-일-피페리딘 -1-일) -메탄온;  148) [2′cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4—yl]-(4-morpholin-4-yl-piperidine-1 -Day) -methanone;
149) [2ᅳ이소프로필ᅳ 6ᅳ(8-메틸-퀴나졸린 -2-일아미노)— 1H-벤즈이미다졸— 4-일] -(4- 모플린 -4-일-피페리딘 -1-일 ) -메탄온；  149) [2'Isopropyl '6' (8-methyl-quinazolin-2-ylamino) — 1H-benzimidazol— 4-yl]-(4-morpholin-4-yl-piperidine-1 -Day) -methanone;
150) N-[2-사이클로프로필— 1-메틸 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H- 벤즈이미다졸 -4—일 ]-2ᅳ모플린 -4-일-아세트아미드;  150) N- [2-cyclopropyl—l-methyl-6- (8-methyl-quinazolin-2-ylamino) -lH-benzimidazol-4-yl] -2 ᅳ morpholin-4-yl-acet amides;
151) 테트라하이드로 -피란 -4-카르복실산 [2-사이클로프로필— 1—메틸 -6— (8-메틸- 퀴나졸린 -2-일아미노) -1H—벤즈이미다졸 -4-일]ᅳ아미드；  151) tetrahydro-pyran-4-carboxylic acid [2-cyclopropyl— 1—methyl-6— (8-methyl-quinazolin-2-ylamino) -1H—benzimidazol-4-yl] ᅳ amide ;
152) 2-사이클로프로필— 6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4- 카르복실산 메틸ᅳ (4-모폴린 -4-일메틸-페닐 ) -아미드； 153) 2-사이클로프로필 -6-(8-메틸-퀴 나졸린 -2-일아미노) -1H-벤즈이미다졸 -4- 카르복실산 메틸— ( 1-메틸ᅳ피를리딘 -3-일 ) -아미드 ; 152) 2-cyclopropyl- 6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazole-4-carboxylic acid methyl ᅳ (4-morpholin-4-ylmethyl-phenyl)- amides; 153) 2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazole-4-carboxylic acid methyl— (1-methylpyrrolidin-3-yl) -Amide;
154) 4-이소프로필-피페라진 -1-카르복실산 [2-사이클로프로필 -1-메틸 -6— (8-메틸- 퀴나졸린 -2-일아미노) -1Hᅳ벤즈이미다졸 -4-일 ] -아미드；  154) 4-isopropyl-piperazin-1-carboxylic acid [2-cyclopropyl-1-methyl-6— (8-methyl-quinazolin-2-ylamino) -1H ᅳ benzimidazol-4-yl ] -Amide;
155) 4-모폴린 -4-일-피 페 리 딘 -1-카르복실산 . [2-사이클로프로필 -6-(8-메틸- 퀴나졸린 -2-일아미노) -1Hᅳ벤즈이미다졸 -4-일 ] -아미드；  155) 4-morpholin-4-yl-piperidine-1-carboxylic acid. [2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H ᅳ benzimidazol-4-yl] -amide;
156) 2-사이클로프로필 -6-(8-메틸-퀴나졸린ᅳ 2-일아미노) -1H-벤즈이 미다졸 -4- 카르복실산 [4-(4-이소프로필―피페라진 -1-일메틸；卜페닐 ] -메틸 -아미드；  156) 2-cyclopropyl-6- (8-methyl-quinazolin 나 2-ylamino) -1H-benzimidazole-4-carboxylic acid [4- (4-isopropyl-piperazin-1-ylmethyl卜 phenyl] -methyl-amide;
157) 4-모폴린—4—일-피 페리딘 -1-카르복실산 [2-사이클로프로필 -1-에틸 -6-(8- 메틸-퀴 나졸린 -2-일아미노) -1H-벤즈이 미다졸 -4-일 ] -아미드 ;  157) 4-morpholine—4—yl-piperidine-1-carboxylic acid [2-cyclopropyl-1-ethyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzi Midazol-4-yl] -amides;
158) 4-메틸-피 페라진 -1-카르복실산 [2-사이클로프로필 -1-메틸 -6ᅳ (8-메틸- 퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4—일 ] -메틸-아미드 ;  158) 4-Methyl-piperazine-1-carboxylic acid [2-cyclopropyl-1-methyl-6 ′ (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4—yl ] -Methyl-amide;
159) 4-이소프로필-피페라진 -1-카르복실산 [2-사이클로프로필 -1-메틸 -6-(8-메틸- 퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4-일 ] -메틸 -아미드；  159) 4-isopropyl-piperazin-1-carboxylic acid [2-cyclopropyl-1-methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl ] -Methyl-amide;
160) 2-메틸 -6-(8-메틸ᅳ퀴나졸린—2-일아미 노) -1H-벤즈이 미다졸— 4—카르복실산 메틸 -(4-모폴린 -4-일메틸ᅳ페닐 ) -아미드；  160) 2-Methyl-6- (8-methyl ᅳ quinazolin-2-ylamino) -1H-benzimidazole- 4-carboxylic acid methyl-(4-morpholin-4-ylmethyl ᅳ phenyl)- amides;
161) 모폴린 -4-카르복실산 메틸 -[2-메틸 -6-(8-메틸 -퀴나졸린— 2-일아미 노)— 1H- 벤즈이 미다졸 -4-일 ] -아미드 ;  161) morpholine-4-carboxylic acid methyl- [2-methyl-6- (8-methyl-quinazolin—2-ylamino) —1H-benzimidazol-4-yl] -amide;
162) 1- [2-사이클로프로필 -1-에 틸 -6-(8-메틸-퀴나졸린 -2ᅳ일아미노) -1H- 벤즈이 미다졸 -4-일 ]— 3—피 리 딘 -2ᅳ일 -우레아；  162) 1- [2-cyclopropyl-1-ethyl-6- (8-methyl-quinazolin-2xylamino) -1H-benzimidazol-4-yl] — 3—pyridin-2xyl- Urea;
163) 피페리 딘 -1-카르복실산 [2-사이클로프로필 -6-(8-메틸—퀴나졸린 -2- 일아미노) -1H-벤즈이 미다졸 -4-일 ] -메틸 -아미드；  163) piperidine-1-carboxylic acid [2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -methyl-amide;
164) 4-메틸-피페라진 -1-카르복실산 메틸 -[2—메틸 -6-(8-메틸-퀴나졸린 -2- 일아미노) -1H—벤즈이 미다졸 -4-일 ] -아미드；  164) 4-methyl-piperazine-1-carboxylic acid methyl-[2—methyl-6- (8-methyl-quinazolin-2-ylamino) -1H—benzimidazol-4-yl] -amide;
165) 2 , 6-다이메틸-모폴린 -4—카르복실산 [2-사이클로프로필 -6-(8-메틸-퀴 나졸린- 2-일아미노) -1H-벤즈이 미다졸 -4-일 ] -메틸-아미드 ;  165) 2, 6-dimethyl-morpholine-4—carboxylic acid [2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -Methyl-amide;
166) 2 , 6-다이메틸-모폴린 -4-카르복실산 메틸 -[2-메틸 -6-(8-메틸-퀴나졸린 -2- 일아미노) -1H-벤즈이미다졸 -4—일] -아미드； 166) 2,6-dimethyl-morpholine-4-carboxylic acid methyl- [2-methyl-6- (8-methyl-quinazolin-2- Monoamino) -1H-benzimidazole-4-yl] -amide;
167) 6-(8-클로로-퀴나졸린 -2-일아미노) -2-메틸 -1H—벤즈이미다졸 -4-카르복실산 메틸 -(4-모폴린 -4-일메틸-페닐 ) -아미드；  167) 6- (8-chloro-quinazolin-2-ylamino) -2-methyl-1H—benzimidazole-4-carboxylic acid methyl- (4-morpholin-4-ylmethyl-phenyl) -amide ;
168) 2-메틸 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4—카르복실산 메틸— (4-모폴린 -4-일-페닐) -아미드;  168) 2-methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazole-4—carboxylic acid methyl— (4-morpholin-4-yl-phenyl) -amide;
169) 테트라하이드로 -피란 -4ᅳ카르복실산 [2—사이클로프로필 -6-(8-메틸-퀴나졸린- 2-일아미노) -1H-벤즈이미다졸 -4-일：卜메틸—아미드；  169) tetrahydro-pyran-4′carboxylic acid [2—cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl ： kmethyl-amide;
170) [4-(4-플루오로-페닐 ) -피페라진— 1-일] [2-메틸 -6-(8-메틸-퀴나졸린ᅳ 2- 일아미노 )-1Η-벤즈이미다졸 -4-일] -메탄은；  170) [4- (4-fluoro-phenyl) -piperazin— 1-yl] [2-methyl-6- (8-methyl-quinazolinyl 2-ylamino) -1Η-benzimidazole-4- General] -methane;
171) [6-(8—메틸-퀴나졸린 -2-일아미노) -1H—인다졸—4-일] -모폴린 -4-일-메탄온; 171) [6- (8—Methyl-quinazolin-2-ylamino) -lH-indazol-4-yl] -morpholin-4-yl-methanone;
172) [2-사이클로프로필ᅳ 6-(8-메틸-퀴나졸린 -2-일아미노) -1H—벤즈이미다졸 -4- 일] [4-(4-플루오로-페닐) -피페라진 -1-일] -메탄은； 172) [2-cyclopropyl ᅳ 6- (8-methyl-quinazolin-2-ylamino) -1H—benzimidazol-4-yl] [4- (4-fluoro-phenyl) -piperazine-1 -Day] -methane;
173) . [2-사이클로프로필ᅳ 6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4- 일] -(4-피리딘 -4-일-피페라진— 1-일 ) -메탄온；  173). [2-cyclopropyl ᅳ 6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl]-(4-pyridin-4-yl-piperazin— 1-yl)- Methanone;
174) 1-{4-[2-사이클로프로필 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸- 4-카보닐 ]ᅳ피페라진 -1-일 }-2-하이드록시 -2—메틸-프로판 -1-온；  174) 1- {4- [2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-carbonyl] pypiperazin-1-yl} -2 -Hydroxy-2 -methyl-propane-1-one;
175) 2-사이클로프로필 -6-(8-메틸-퀴나졸린 -2-일아미노) -1Hᅳ벤즈이미다졸 -4- 카르복실산 (3-플루오로 -5—모폴린 -4-일-페닐 ) -아미드；  175) 2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H -benzimidazole-4-carboxylic acid (3-fluoro-5-morpholin-4-yl-phenyl ) -Amide;
176) [2—에틸 -6-(8-메틸-퀴나졸린 -2-일아미노) -2H—인다졸 -4-일] -모폴린 -4-일- 메탄온;  176) [2—ethyl-6- (8-methyl-quinazolin-2-ylamino) -2H-indazol-4-yl] -morpholin-4-yl-methanone;
177) [ 1-에틸 -6ᅳ ( 8-메틸-퀴나졸린 -2-일아미노) - 1H-인다졸 -4-일] -모폴린 -4-일- 메탄온;  177) [1-ethyl-6 ′ (8-methyl-quinazolin-2-ylamino) -1H-indazol-4-yl] -morpholin-4-yl-methanone;
178) 1-(3-플루오로 -5-모폴린 -4-일-페닐) -3-[2ᅳ메틸ᅳ6-(8-메틸-퀴나졸린 -2- 일아미노) -1H-벤즈이미다졸 -4-일] -우레아;  178) 1- (3-Fluoro-5-morpholin-4-yl-phenyl) -3- [2 ᅳ methyl ᅳ 6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazole -4-yl] -urea;
179) Nᅳ [2-사이클로프로필 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4- 일] -3—모폴린 -4-일-벤즈아미드;  179) N '[2-cyclopropyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -3—morpholin-4-yl-benzamide;
180) N-[2-메틸 -6-(8-메틸-퀴나졸린 -2-일아미노) -1H-벤즈이미다졸 -4-일] -3- 모폴린 -4-일-벤즈아미드; 180) N- [2-methyl-6- (8-methyl-quinazolin-2-ylamino) -1H-benzimidazol-4-yl] -3- Morpholin-4-yl-benzamide;
181) 모폴린 -4ᅳ카르복실산 [2-에틸ᅳ 6-(8ᅳ메틸-퀴나졸린 -2-일아미노) -2H-인다졸- 4-일] -아미드;  181) morpholine-4′carboxylic acid [2-ethyl ᅳ 6- (8′methyl-quinazolin-2-ylamino) -2H-indazol-4-yl] -amide;
182) 1-에틸 -6-(8—메틸—퀴나졸린— 2-일아미노) -1H-인다졸 -4-카르복실산 (3- 플루오로ᅳ 5-모폴린 -4—일-페닐 ) -아미드；  182) 1-Ethyl-6- (8-methyl-quinazolin- 2-ylamino) -lH-indazol-4-carboxylic acid (3-fluoro ᅳ 5-morpholine-4-yl-phenyl)- amides;
183) 1— [2-사이클로프로필ᅳ6-(8ᅳ메틸ᅳ퀴나졸린 -2ᅳ일아미노) -1H-벤즈이미다졸 -4ᅳ 일] _3-(3-플루오로 -5-모폴린 -4-일-페닐 ) -우레아; 및  183) 1— [2-cyclopropyl ᅳ 6- (8 ᅳ methyl ᅳ quinazolin-2xylamino) -1H-benzimidazole-4xyl] _3- (3-fluoro-5-morpholine-4- Phenyl) -urea; And
184) 모폴린 -4-카르복실산 [2-사이클로프로필 -6-(4ᅳ트리플루오로메틸-피리미딘- 2-일아미노) -1H-벤즈이미다졸 -4-일]—아미드 .  184) morpholine-4-carboxylic acid [2-cyclopropyl-6- (4'trifluoromethyl-pyrimidin- 2-ylamino) -1H-benzimidazol-4-yl] —amide.
7. 제 1 항의 화합물, 또는 이의 약학적으로 허용가능한 염 이성질체， 수화물 또는 용매화물의 단백질 키나제에 의해 유도된 비정상적인 세포 반응과 관련된 질환의 예방 또는 치료용 용도. 7. Use for the prevention or treatment of diseases associated with abnormal cellular responses induced by the protein kinase of the compound of claim 1, or a pharmaceutically acceptable salt isomer, hydrate or solvate thereof.
8. 제 7 항에 있어서， 상기 단백질 키나제가 SYK, JAK3, FLT3, FLT2, PDGFR α (PDGFRA) , TRKA (NTRKl), KDR, CD 2/cycA, AurA (AURKA) ERK, PI3K, Raf, PYK2 및 RET로 이루어진 군에서 선택되는 것을 특징으로 하는， 용도. 8. The method of claim 7, wherein the protein kinase is SYK, JAK3, FLT3, FLT2, PDGFR α (PDGFRA), TRKA (NTRKl), KDR, CD 2 / cycA, AurA (AURKA) ERK, PI3K, Raf, PYK2 and Use, characterized in that selected from the group consisting of RET.
9. 제 7 항에 있어서, 상기 질환이 면역질환， 자가면역질환， 염증질환， 골질환， 대사이상， 신경정신질환， 퇴행성 뇌질환， 암， 심장질환， 알레르기질환， 천식, 알츠하이머， 및 호르몬 관련 질환으로 이루어진 군에서 선택되는 것을 특징으로 하는， 용도. 9. The disease according to the above 7, wherein the disease is immune, autoimmune, inflammatory, bone, metabolic, neuropsychiatric, degenerative brain, cancer, heart, allergic, asthma, Alzheimer's, and hormone-related. Use, characterized in that selected from the group consisting of diseases.
10. 유효성분으로서 제 1 항의 화합물， 또는 이의 약학적으로 허용가능한 염， 이성질체， . '수화물 또는 용매화물 및 약학적으로 허용되는 담체를 함유하는, 단백질 키나제에 의해 유도된 비정상적인 세포 반응과 관련된 질환의 예방 또는 치료용 약학 조성물. 10. The compound of claim 1, or a pharmaceutically acceptable salt, isomer thereof, as an active ingredient. "Hydrate or solvate thereof and containing a pharmaceutically acceptable carrier, the pharmaceutical composition for preventing or treating diseases associated with an abnormal cellular responses induced by protein kinases.
11. 제 1 항의 화합물, 또는 이의 약학적으로 허용가능한 염， 이성질체, 수화물 또는 용매화물의 유효량을 이를 필요로 하는 포유동물에게 투여하는 것을 포함하는 단백질 키나제에 의해 유도된 비정상적인 세포 반웅과 관련된 질환의 예방 또는 치료방법. 11. A disease associated with abnormal cell reactions induced by protein kinases comprising administering to a mammal in need thereof an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof. Prevention or treatment.
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